2-Carbamoyloxymethyl-penicillin derivatives

ABSTRACT

Penicillin sulfoxide esters are reacted with an isocyanate to produce the corresponding (substituted)-2-carbamoyloxymethylpenam, the corresponding (substituted)-3-carbamoyloxycepham or the corresponding 3-methylcephem. The 6- or 7-side-chain of these products may be cleaved to give the corresponding 6-amino (penams) or 7-amino (cephams and cephems) compounds, and the latter may be reacylated to produce different 6-acyl-2-carbamoyloxymethyl penams, 7-acyl-3-carbamoyloxy cephams and 7-acyl-3-methylcephems. The substituent groups may be removed from the (substituted)-2-carbamoyloxypenams or the (substituted)-3-carbamoyloxycephams to give the corresponding free 2-carbamoyloxymethylpenams or 3-carbamoyloxycephams, respectively.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to 2-carbamoyloxymethylpenicillins,3-carbamoyloxycephalosporins and desacetoxy cephalosporins, and to theirpreparation by reaction of a penicillin sulfoxide with an isocyanate.

2. Description of the Prior Art

(A) U.S. Pat. No. 3,275,626 discloses, inter alia, the preparation of2-acyloxymethyl penams, 3-acyloxy cephams and 3-methyl-Δ³ -cephems byheating a penicillin sulfoxide in the presence of an acid, an acidanhydride, or the like. Generally, when the starting penicillinsulfoxide is reacted in its free acid or salt form the product isdecarboxylated, while reaction of the starting penicillin sulfoxide inits esterified form yields a product retaining the esterified carboxylmoiety. The ester group is subsequently removed by, for example,hydrolysis or catalytic hydrogenation.

(B) U.K. Pat. No. 1,409,415 discloses a process for preparing3-methyl-Δ³ -cephems by heating with an anhydrous acid a penicillinsulfoxide having its carboxyl group protected by a group of the formula##STR1## in which R₄ and R₅ are the same or different and represent,inter alia, (lower)alkyl, cycloalkyl, phenyl, phenyl(lower)alkyl,(lower)alkoxy, (lower)alkylthio, phenoxy, phenyl(lower)alkoxy, halogen,or a 6-substituted aminopenicillanic sulfoxide-3-carbonyloxy group, orR⁴ and R⁵ taken together with M₁ represent the residue of a ring system,and M₁ is a boron, aluminum or phosphorus atom; a group of the formula##STR2## in which R₄, R₅ and R₆ are as described above for R₄ and R₅, orR₄ and R₅ taken together with M₂ represent the residue of a ring system,or R₄ and R₅ together represent oxygen (═O) or sulfur (═S), and M₂ issilicon, sulfur, germanium or tin, or a carbon atom when R₄ and R₅together represent oxygen or sulfur; a group of the general formula##STR3## in which R₄ and R₅ are as described above and R₇ and R₈ areeach halogen or a 6-substituted aminopenicillanicsulfoxide-3-carbonyloxy group, or R₇ and R₈ taken together with M₃represent the residue of a ring system, or R₇ and R₈ together representoxygen (═O) or sulfur (═S), and M₃ represents phosphorus or tungsten; agroup of the general formula ##STR4## in which R₉ is (lower)alkyl,cycloalkyl, phenyl, phenyl(lower)alkyl, (lower)alkoxy, (lower)alkylthio,phenoxy or phenyl(lower)alkoxy, and M₄ represents sulfur; or ##STR5##

The reaction is run under anhydrous conditions in the presence of silylcompounds which are capable of rapid reaction with the water formedduring the ring enlargement reaction and which form either neutral orbasic compounds upon hydrolysis. In a preferred embodiment the reactionis conducted in the presence of an excess of a nitrogen containing base.The carboxyl protecting group is subsequently removed by simplehydrolysis.

(C) U.K. Pat. No. 1,421,080 discloses a process for the preparation ofcompounds of the formula ##STR6## in which either R₁ is a hydrogen atomand R₂ is a phenacetyl, phenoxyacetyl, trityl, optionally protectedα-aminophenacetyl radical (which may contain one or more nuclearsubstitutents selected from hydroxyl, alkoxy, alkyl-mercapto and halogenradicals), thienylacetyl or tert.-butoxycarbonyl radical; or R₁ and R₂form, together with the nitrogen atom to which they are attached, aphthalimido or succinimido group; and R₃ is a benzyl, methoxybenzyl,nitrobenzyl, diphenylmethyl, trityl, β,β,β-trichloroethyl, cyanomethyl,9-fluorenyl, tert.-butyl phenacyl, chlorophenacyl, bromophenacyl,nitrophenacyl, phenylphenacyl, alkoxyphenacyl, or trimethylsilylradical; in which process a 6-acylaminopenicillanic acid ester of thegeneral formula: ##STR7## (in which R₁, R₂ and R₃ are as defined above)is heated to 60°-150° C. in the presence as a catalyst of a phenol ofthe general formula: ##STR8## in which R₄, R₅, R₆, R₇ and R₈ areidentical or different radicals selected from hydrogen, nitro, nitrileand halogen radicals, alkyl and haloalkyl radicals, carbalkoxy radicals,alkylcarbonyl radicals, alkylsulphonyl radicals, benzoyl,phenylsulphonyl and carbophenoxy radicals, and phenyl radicalsoptionally carrying one or more substituents selected from the radicalsgiven therein as possible meanings for R₄ -R₈ ; provided that in thegeneral formula only one of R₄ -R₈ can be a halogen atom and not morethan two of R₄ -R₈ can be hydrogen atoms.

(D) U.S. Pat. No. 4,010,156 discloses a process for preparing3-halo-3-methylcepham derivatives of the formula ##STR9## in which R¹ ishydrogen or an organic acyl radical; R² is hydrogen or, taken togetherwith R¹ -N, may represent phthalimido or ##STR10## in which R⁴ and R⁵are hydrogen or (lower)alkyl and R⁶ is phenyl or 1,4-cyclohexadienyl; R³is hydroxy, (lower)alkoxy, 2,2,2-trichloroethoxy, aryloxy, aralkoxy,alkoxyaralkoxy, mono- or di-(lower)alkylamino, arylamino saccharimido,phthalimido or OM in which M is an alkali metal cation, an alkalineearth metal cation or the ammonium cation; and A is chloro, bromo oriodo. The compounds are prepared by heating the corresponding penicillinsulfoxide of the formula ##STR11## in which R¹, R² and R³ are as definedabove in a polyhaloalkane solvent in the presence of an equimolar amountof any of certain specified quaternary ammonium salt catalysts. The3-halo compound is then dehydrohalogenated to form the correspondingcephem compound. Alternatively, the cephem compound may be produced inone step from the penicillin sulfoxide by utilizing a basic catalystsuch as pyridine instead of the quaternary ammonium salt catalyst.

(E) U.S. Pat. No. 3,997,533 discloses a process for convertingpenicillin sulfoxide esters to the corresponding 3-methyl-Δ³ -cephemcompound by heating in the presence of a heavy metal salt catalyst ofthe formula

    Me(R"SO.sub.3).sub.n

wherein Me is copper, silver, gold, zinc, cadmium, mercury, thallium,tin, lead, iron, cobalt or nickel; R" is (lower)alkyl,fluoro(lower)alkyl or substituted or unsubstituted phenyl or naphthyl;and n is 1-3 depending on the valence of Me.

(F) Japanese Patent Publication No. 50-53387 discloses a process forpreparing compounds of the formula ##STR12## in which R₁ is hydrogen,acyl or substituted silyl and R₂ is hydrogen, alkyl, aryl, aralkyl orsubstituted silyl, by heating a penicillin sulfoxide of the formula##STR13## in which R₁ and R₂ are as described above, in a non-reactiveorganic solvent, with 1-5 equivalents of an isocyanate of the formula

    R.sub.3 --(NCO).sub.n

in which R₃ is alkyl, aryl, aralkyl, alkylene or arylene and n is 1-3.It is stated that the reaction is accelerated by the addition of 0.1mole of pyridine, quinoline or isoquinoline per mole of penicillinsulfoxide. Specifically mentioned isocyanates are phenyl isocyanate,toluene-2,4-diisocyanate, methyl isocyanate, isobutyl isocyanate andhexamethylene diisocyanate. The patent does not teach the use of acylisocyanates, substituted sulfonyl, sulfinyl or sulfenyl isocyanates, orsubstituted metal or non-metal isocyanates.

It has been our finding with the above reaction that phenyl isocyanateis not sufficiently reactive to transform a penicillin sulfoxide esterunless a base is present. The transformation of penicillin sulfoxides tocephalosporins is accompanied by the elimination of a mole of water forevery mole of 3-methylcephalosporin produced. This water, when scavengedby an alkyl or aryl isocyanate (as in the above patent), gives an alkylor aryl amine, which in turn may be scavenged by excess isocyanates orby the β-lactam. The latter unwanted reaction may account for pooryields in the above process for ring expansion. Because of this, thereaction of alkyl or aryl isocyanates with penicillin sulfoxides is ofno commercial interest. A further drawback of the alkyl and arylisocyanates is their extreme toxicity. Isocyanates which do not givealkyl or aryl amines, or their derivatives, on hydrolysis wereconsidered by us to offer new prospects not compromised by theproduction of unwanted side products. Activated isocyanates such as acylisocyanates, substituted sulfonyl, sulfinyl or sulfenyl isocyanates, andsubstituted metal and non-metal isocyanates offer a potential which hashitherto been unexamined.

(G) Various excellent reviews of prior art processes for rearrangementsand/or ring expansion of penicillin sulfoxides are available. See, forexample, R. D. G. Cooper, et al., Accounts of Chemical Research, 6, 32(1973) and Chapter 5, entitled "Rearrangements of Cephalosporins andPenicillins", in the book Cephalosporins and Penicillins, E. H. Flynn,ed., Academic Press, New York, 1972.

(H) W. German OLS No. 2,704,712 discloses, inter alia the reaction of3-hydroxymethyl Δ³ -cephems with certain isocyanates to produce thecorresponding substituted 3-carbamoyloxymethyl Δ³ -cephems, withoptional removal of the substituent group. A specific example was asfollows (R¹ =tritylamino): ##STR14##

DETAILED DESCRIPTION

This invention relates to β-lactam antibiotics. More specifically, itrelates to the reaction of a penicillin sulfoxide with an isocyanate toproduce the corresponding 2-carbamoyloxymethylpenam, the corresponding3-carbamoyloxycepham or the corresponding 3-methylcephem. In anotheraspect, this invention relates to the cleavage of the above products toproduce the corresponding compounds having a free amino group in the6-position (penams) or 7-position (cephams and cephems), and to theacylation of the free amino groups of these latter compounds to producestill different 6-acyl-2-carbamoyloxymethylpenams,7-acyl-3-carbamoyloxycephams and 7-acyl-3-methylcephems.

The reactions may be better visualized by reference to the followinggeneral reaction schemes. ##STR15##

In the above general reaction schemes,

R¹ is hydrogen and

R² is an amino-blocking group or a conventional acyl group known in thepenicillin or cephalosporin art, or

R¹ and R², taken together with the nitrogen to which they are attached,may form a phthalimido group, a succinimido group or a group of theformula ##STR16## in which R⁹ and R¹⁰ are (lower)alkyl, R¹¹ is1,4-cyclohexadienyl, substituted or unsubstituted phenyl, or asubstituted or unsubstituted heterocyclic group containing one or morehetero atoms such as sulfur, oxygen and/or nitrogen, e.g. thienyl,furyl, tetrazolyl, thiazolyl or thiadiazolyl; and R¹² is hydrogen, analdehydo group or a nitroso group;

R³ is hydrogen, (lower)alkoxy, (lower)alkylthio or ##STR17## in whichR¹³ is substituted or unsubstituted (lower)alkyl or aryl; --COOR⁴ is aprotected carboxyl group or a derivative of a carboxyl group;

R⁵ is an acyl group, a thioacyl group, a substituted sulfonyl, sulfinylor sulfenyl group, or a substituted metal or non-metal atom having avalence of from 2 to 5;

n is an integer of from 1 to 4;

R⁶ is hydrogen, is the same as R⁵, or is ##STR18## in which R¹, R², R³and R⁷ are as defined above, and a and b are the same or different andrepresent an integer from 0 to n-1, wherein n is as defined above,provided that the sum of a and b is not greater than n-1;

R⁷ is hydrogen or the same as R⁴ ; and ##STR19## is a conventional acylgroup known in the penicillin and cephalosporin art.

The isocyanates of Formula II, above, include, for example, those of thefollowing formulae.

    (a) W.sub.2 --M.sub.2 --NCO

in which M₂ is a divalent metal or non-metal atom (and preferably sulfuror selenium) and W₂ is a substituted or unsubstituted alkyl, aryl oraralkyl group, or an isocyanate group. Examples of isocyanates fallingwithin this class are trichloromethylsulfenyl isocyanate,dichloromethylsulfenyl isocyanate, trifluoromethylsulfenyl isocyanate,difluoromethylsulfenyl isocyanate, 2,4-dinitrophenylsulfenyl isocyanate,sulfenyl diisocyanate, selenium diisocyanate, chloromethyl seleniumisocyanate, dichloromethyl selenium isocyanate trichloromethyl seleniumisocyanate, mono-, di- or trifluoromethyl selenium isocyanate, and thelike. ##STR20## in which M₃ is a trivalent metal or non-metal atom, W₃and X₃ are the same or different and represent a substituted orunsubstituted (lower)alkyl, aryl, ar(lower)alkyl, cycloalkyl,(lower)alkoxy, aryloxy, ar(lower)alkoxy, (lower)alkylthio, orar(lower)alkylthio group, or an isocyanate group; or W₃ and X₃, takentogether with M₃, represent a ring system. Examples of isocyanatesfalling within this class are phosphorous triisocyanate, borontriisocyanate, antimony triisocyanate, aluminum triisocyanate, (C₄ H₉)₂BNCO, (C₂ H₅)₂ AlNCO, C₄ H₉ B(NCO)₂, C₂ H₅ Al(NCO)₂, (C₆ H₅)₂ PNCO, (C₂H₅ O)₂ BNCO, (C₆ H₅ CH₂ O)₂ PNCO, (C₂ H₅ S)₂ PNCO, (CH₃ O)₂ PNCO, ClCH₂CH₂ OP(NCO)₂, ##STR21## and the like. ##STR22## in which M₄ is atetravalent metal or non-metal atom, W₄, X₄ and Y₄ are the same ordifferent and represent a substituted or unsubstituted (lower)alkyl,aryl, ar(lower)alkyl, cycloalkyl, (lower)alkoxy, aryloxy,ar(lower)alkoxy, (lower)alkylthio, or ar(lower)alkylthio group, or anisocyanate group; or W₄ and X₄, taken together with M₄, represent a ringsystem; or W₄, X₄ and Y₄, taken together with M₄, represent a ringsystem other than phenyl or substituted phenyl; or W₄ and X₄, takentogether, represent ═O, ═S or ═NW₄. Examples of isocyanates within thisclass are:

(1) acyl isocyanates and thioacyl isocyanates such as acetyl isocyanate,mono-, di- or trichloroacetyl isocyanate, mono-, di- or trifluoroacetylisocyanate, propionyl and butyryl isocyanates and their chlorinated orfluorinated analogs, phenylacetyl isocyanate, cyanoacetyl isocyanate,benzoyl isocyanate, p-nitrobenzoyl isocyanate, 2,4-dinitrobenzoylisocyanate, benzyloxycarbonyl isocyanate, p-nitrobenzyloxycarbonylisocyanate, methoxycarbonyl isocyanate, chloromethoxycarbonylisocyanate, carbonyl diisocyanate, cyanocarbonyl isocyanate, and thelike, as well as their thio analogs, e.g. trichlorothioacetylisocyanate, chloromethoxythiocarbonyl isocyanate, and the like;

(2) sulfinyl isocyanates of the formula ##STR23## in which Y₄ is asdefined above;

(3) metal and non-metal tetraisocyanates such as Sn(NCO)₄, Se(NCO)₄,Ti(NCO)₄, Ge(NCO)₄, Si(NCO)₄, and the like;

(4) substituted metal and non-metal isocyanates of the formula ##STR24##in which M₄ is as defined above and W_(4a), X_(4a) and Y_(4a) are thesame or different and represent substituted or unsubstituted(lower)alkyl, (lower)alkoxy or (lower)alkylthio; or W_(4a) or bothW_(4a) and X_(4a), may be an isocyanate group; or W_(4a) and X_(4a),taken together with M₄, may represent a ring system. Examples ofisocyanates falling within this class are (CH₃)₃ SnNCO, (CH₃)₃ SbNCO,(CH₃)₃ GeNCO, (CH₃)₃ TiNCO, (CH₃)₂ Sn(NCO)₂, (CH₃)₂ Sb(NCO)₂, CH₃Ti(NCO)₃, CH₃ Ge(NCO)₃, (C₂ H₅ O)₃ SnNCO, (C₂ H₅ O)₃ SbNCO, (C₂ H₅ S)₃TiNCO, (C₂ H₅ S)₃ GeNCO, (ClC₂ H₄)₃ SbNCO, ##STR25## and the like;

(5) silyl isocyanates of the formula

    (W.sub.4).sub.m --Si--(NCO).sub.4-m

in which W₄ is as described above and m is an integer of from 1 to 3.Examples of isocyanates falling within this class include trimethylsilylisocyanate, dimethylsilyl diisocyanate, methylsilyl triisocyanate,trimethoxysilyl isocyanate, triethoxysilyl isocyanate, triethylsilylisocyanate, diphenylsilyl diisocyanate, dibenzyloxy diisocyanate,triphenylsilyl isocyanate, tribenzylsilyl isocyanate, (ClC₂ H₄)₃ SiNCO,(ClC₂ H₄ O)₂ Si(NCO)₂, (C₆ H₅ O)₂ Si(NCO)₂, ##STR26## and the like; and

(6) ring compounds of the formula ##STR27## in which M_(3a) is nitrogen,boron, phosphorus or antimony. ##STR28## in which M₅ is a pentavalentmetal or non-metal atom and W₅, X₅, Y₅ and Z₅ are the same or differentand represent a substituted or unsubstituted (lower)alkyl, aryl,aryloxy, (lower)alkoxy, or (lower)alkylthio group, or an isocyanategroup; or W₅ and X₅, taken together with M₅, represent a ring system; orW₅ and X₅, taken together, represent ═O or ═S. Examples of isocyanateswithin this class are (C₄ H₉)₃ Sb(NCO)₂, (CH₃)₄ SbNCO, (ClC₂ H₄)₃Sb(NCO)₂, ##STR29## and the like. ##STR30## in which R¹⁴ is asubstituted or unsubstituted (lower)alkyl, aryl, ar(lower)alkyl,cycloalkyl, (lower)alkoxy, aryloxy, ar(lower)alkoxy, (lower)alkylthio,or ar(lower)alkylthio group, or an isocyanate group. Examples ofisocyanates falling within this class are methylsulfonyl isocyanate,chloromethylsulfonyl isocyanate, phenylsulfonyl isocyanate,p-nitrophenylsulfonyl isocyanate, 2,4-dinitrophenylsulfonyl isocyanate,toluenesulfonyl isocyanate, phenoxysulfonyl isocyanate,benzyloxysulfonyl isocyanate, ethoxysulfonyl isocyanate,ethylthiosulfonyl isocyanate, sulfonyl diisocyanate, and the like.

In one preferred embodiment of the invention, in the penicillinsulfoxide ester starting material of Formula I, R¹ and R², takentogether with the nitrogen to which they are attached, may form aphthalimido group, a succinimido group or a group of the formula##STR31## in which R⁹ and R¹⁰ are (lower)alkyl, R¹¹ is1,4-cyclohexadienyl, substituted or unsubstituted phenyl, or asubstituted or unsubstituted heterocyclic group containing one or morehetero atoms such as sulfur, oxygen and/or nitrogen, e.g. thienyl,furyl, tetrazolyl, thiazolyl or thiadiazolyl, and R¹² is hydrogen, analdehydo group or a nitroso group.

In a more preferred embodiment R¹ and R², taken together with thenitrogen to which they are attached, form a group of the formula##STR32## in which R⁹ and R¹⁰ are as defined above (but preferably areeach methyl), R¹² is as defined above (but preferably is hydrogen, andR¹¹ is as defined above (but preferably is 1,4-cyclohexadienyl, phenyl,p-hydroxyphenyl, thienyl, furyl, tetrazolyl, thiazolyl or thiadiazolyl).Most preferably, R¹¹ is phenyl or p-hydroxyphenyl. It is also preferredthat R⁶ be hydrogen.

In another preferred embodiment of the invention, in the penicillinsulfoxide ester starting material of Formula I, R¹ is hydrogen and R² isan acyl group of the formula ##STR33## in which r is 0 or 1, s is aninteger of from 0 to 6, t is 0 or 1, A is oxygen or sulfur, R¹⁶ isamino, substituted amino, acylamino, hydroxy, azido, halogen, carboxy,carbamoyl, guanidino, sulfo, sulfamino, phosphono, acyloxy, tetrazolyl,carboalkoxy, or the like, and R¹⁵ is hydrogen, or a substituted orunsubstituted alkyl, aryl, aralkyl, cycloalkyl, heterocyclyl orheterocyclylalkyl group.

In a more preferred embodiment, the acyl group of Formula XIV has thestructure ##STR34## in which R¹⁵ is as defined above. Group R¹⁵ may beunsubstituted or may be substituted by such groups as OH, SH, SR (whereR is alkyl or aryl), alkyl, alkoxy, aryl, halo, cyano, carboxy, nitro,sulfoamino, carbamoyl, sulfonyl, azido, amino, substituted amino,haloalkyl, carboxyalkyl, carbamoylalkyl, N-substituted carbamoylalkyl,guanidino, N-substituted guanidino, guanidinoalkyl, or the like.Examples of suitable acyl groups of Formula XV are those in which R¹⁵ isbenzyl, p-hydroxybenzyl, 4-amino-4-carboxybutyl, methyl, cyanomethyl,n-amyl, n-heptyl, ethyl, propyl, isopropyl, 3- or 4-nitrobenzyl,phenethyl, β,β-diphenylethyl, methyldiphenylmethyl, triphenylmethyl,2-methoxyphenyl, 2,6-dimethoxyphenyl, 2,4,6-trimethoxyphenyl,3,5-dimethyl-4-isoxazolyl, 3-butyl-5-methyl-4-isoxazolyl,5-methyl-3-phenyl-4-isoxazolyl,3-(2-chlorophenyl)-5-methyl-4-isoxazolyl,3-(2,6-dichlorophenyl)-5-methyl-4-isoxazolyl, 2- or3-(5-methylthienyl)methyl, D-4-amino-4-carboxybutyl,D-4-N-benzoylamino-4-carboxy-n-butyl, p-aminobenzyl, o-aminobenzyl,m-aminobenzyl, (3-pyridyl)methyl, 2-ethoxy-1-naphthyl,3-carboxy-2-quinoxalinyl,3-(2,6-dichlorophenyl)-5-(2-furyl)-4-isoxazolyl, 3-phenyl-4-isoxazolyl,5-methyl-3-(4-quanidinophenyl)-4-isoxazolyl, 4-guanidinomethylphenyl,4-guanidinomethylbenzyl, 4-quanidinobenzyl, 4-guanidinophenyl,2,6-dimethoxy-4-guanidinophenyl, o-sulfobenzyl, p-carboxymethylbenzyl,p-carbamoylmethylbenzyl, m-fluorobenzyl, m-bromobenzyl, p-chlorobenzyl,p-methoxybenzyl, 1-naphthylmethyl, 3-isothiazolylmethyl,4-isothiazolylmethyl, 5-isothiazolylmethyl, 4-pyridylmethyl, 5-isoxazolylmethyl, 4-methoxy-5-isoxazolylmethyl,4-methyl-5-isoxazolymethyl, 1-imidazolylmethyl, 2-benzofuranylmethyl,2-indolylmethyl, 2-phenylvinyl, 2-phenylethynyl,2-(5-nitrofuranyl)vinyl, phenyl, o-methoxyphenyl, o-chlorophenyl,o-phenylphenyl, p-aminomethylbenzyl, 1-(5-cyanotriazolyl)methyl,difluoromethyl, dichloromethyl, dibromomethyl,1-(3-methylimidazolyl)methyl, 2- or 3-(5-carboxymethylthienyl)methyl, 2-or 3-(4-carbamoylthienyl)methyl, 2- or 3-(5-methoxythienyl)methyl, 2- or3-(4-chlorothienyl)methyl, 2- or 3-(5-sulfothienyl)methyl, 2- or3-(5-carboxythienyl)methyl, 3-(1,2,5-thiadiazolyl)methyl,3-(4-methoxy-1,2,5-thiadiazolyl)methyl, 2-furylmethyl,2-(5-nitrofuryl)methyl, 3-furylmethyl, 2-thienylmethyl, 3-thienylmethyl,tetrazolylmethyl, cyclopentyl, cyclohexyl, cycloheptyl cyclohexylmethyl,cyclohexylpropyl, dihydrobenzyl, dihydrophenylmethyl, tolylmethyl,xylylmethyl, tetrahydronaphthylmethyl, piperazinylmethyl,pyrrolidinylmethyl, benzothiazolylmethyl, benzoxazolylmethyl, and 1H (or2H)-tetrazolylmethyl.

In another more preferred embodiment, the acyl group of Formula XIV hasthe structure ##STR35## wherein R¹⁵, A and s are as defined above.Examples of suitable groups of the formula R¹⁵ A(CH₂)_(s) -- includemethoxymethyl, methylthiomethyl, cyclohexylthiomethyl,cyclohexyloxymethyl, dihydrophenoxymethyl, dihydrophenylthiomethyl,cyclopentyloxy, cyclohexyloxy, dihydrophenoxy, benzyloxy, xylyloxy,tolyloxy, naphthoxy, phenylthiomethyl, butylmercaptomethyl,allylthiomethyl, 2-furyloxy, 8-quinolyloxy, pyridylmethoxy,trichloroethoxy, 1-cyclopropylethoxy, p-nitrobenzyloxy,o-chlorobenzyloxy, o-nitrobenzyloxy, p-methoxybenzyloxy,3,4-dimethoxybenzyloxy, α-chlorocrotylmercaptomethyl, phenoxymethyl,phenoxyethyl, phenoxybutyl, phenoxybenzyl, diphenoxymethyl,dimethylmethoxymethyl, dimethylbutoxymethyl, dimethylphenoxymethyl,4-guanidinophenoxymethyl, 4-pyridylthiomethyl,p-(carboxymethyl)phenoxymethyl, p-(carboxymethyl)phenylthiomethyl,2-thiazolylthiomethyl, p-(sulfo)phenoxymethyl,p-(carboxy)phenylthiomethyl, p-(carboxymethyl)phenoxymethyl,p-(carboxymethyl)phenylthiomethyl, 2-pyrimidinylthiomethyl,phenethylthiomethyl and 1-(5,6,7,8-tetrahydronaphthyl)oxomethyl.

In another more preferred embodiment, the acyl group of Formula XIV hasthe structure ##STR36## wherein R¹⁵ and R¹⁶ are as defined above.Examples of suitable groups of the formula ##STR37## includeα-aminobenzyl, α-amino-2-thienyl, α-methylaminobenzyl,α-amino-methylmercaptopropyl, α-amino-3- or 4-chlorobenzyl, α-amino-3 or4-hydroxybenzyl, α-amino-2,4-dichlorobenzyl, α-amino-3,4-dichlorobenzyl,β(-)-α-hydroxybenzyl, α-carboxybenzyl, α-amino-3-thienyl,α-amino-2-thienyl, D-(-)-α-amino-3-chloro-4-hydroxybenzyl,D(-)-α-amino-3-thienyl, 1-aminocyclohexyl, α-(5-tetrazolyl)benzyl,2-(α-carboxy)thienylmethyl, 3-(α-carboxy)furylmethyl, α-sulfaminobenzyl,α-sulfamino-3-thienyl, α-(N-methylsulfamino)benzyl,D(-)-α-guanidino-2-thienyl, D(-)-α-guanidinobenzyl,α-guanylureidobenzyl, α-hydroxybenzyl, α-azidobenzyl, α-fluorobenzyl,4-(5-methoxy-1,3-oxadiazolyl)-aminomethyl,4-(5-methoxy-1,3-oxadiazolyl)-hydroxymethyl,4-(5-methoxy-1,3-oxadiazolyl)carboxymethyl,4-(5-methoxy-1,3-sulfadiazolyl)-aminomethyl,4-(5-methoxy-1,3-sulfadiazolyl)-hydroxymethyl,4-(5-methoxy-1,3-sulfadiazolyl)-carboxymethyl,2-(5-chlorothienyl)-aminomethyl, 2-(5-chlorothienyl)-hydroxymethyl,2-(5-chlorothienyl)carboxymethyl, 3-(1,2-thiazolyl)-aminomethyl,3-(1,2-thiazolyl)-hydroxymethyl, 3-(1,2-thiazolyl)-carboxymethyl,2-(1,4-thiazolyl)aminomethyl, 2-(1,4-thiazolyl)-hydroxymethyl,2-(1,4-thiazolyl)carboxymethyl, 2-benzothienylaminomethyl,2-benzothienylhydroxymethyl, 2-benzothienylcarboxymethyl, α-sulfobenzyl,and α-phosphonobenzyl.

If the acyl group contains a functional group, such as amino, hydroxy,mercapto or carboxy, the functional group may be protected with anappropriate protective group. Because the acyl side-chain maysubsequently be cleaved to produce the free amino compound (which may,if desired, be re-acylated with a different side-chain), it is notalways necessary to protect reactive substituent groups in theside-chain.

Suitable protective groups for the amino radical include any of theconventional protective groups such as those acyl groups which caneasily be split off (e.g. trichloroethoxycarbonyl, benzyloxycarbonyl,p-toluenesulfonyl, p-nitrobenzyloxycarbonyl, o-chlorobenzyloxycarbonyl,o-nitrophenylsulfenyl, chloroacetyl, trifluoroacetyl, formyl,tert-butoxycarbonyl, p-methoxybenzyloxycarbonyl,3,4-dimethoxybenzyloxycarbonyl, 4-phenylazobenzyloxycarbonyl,4-(4-methoxyphenylazo)benzyloxycarbonyl,pyridine-1-oxide-2-methoxy-carbonyl, 2-pyridylmethoxycarbonyl,2-furyloxycarbonyl, diphenylmethoxycarbonyl,1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl,1-cyclopropylethoxycarbonyl, phthaloyl, succinyl, 1-adamantyloxycarbonylor 8-quinolyloxycarbonyl), or other radicals which can easily be splitoff (e.g. trityl, 2-nitrophenylthio, 2,4-dinitrophenylthio,2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene,2-hydroxy-1-naphthylmethylene, 3-hydroxy-4-pyridylmethylene,1-methoxycarbonyl-2-propylidene, 1-ethoxycarbonyl-2-propylidene,3-ethoxycarbonyl-2-butylidene, 1-acetyl-2-propylidene,1-benzoyl-2-propylidene, 1-[N-(2-methoxyphenyl)carbamoyl]-2-propylidene,1-[N-(4-methoxyphenyl)carbamoyl]-2-propylidene,2-ethoxycarbonylcyclohexylidene, 2-ethoxycarbonylcyclopentylidene,2-acetylcyclohexylidene, 3,3-dimethyl-5-oxocyclohexylidene, or mono- orbis-trialkylsilyl). Other conventional amino protecting groups such asthose described in "Protective Groups in Organic Chemistry," J. F. W.McOmie, Ed., Plenum Press, New York, New York, 1973 Chapter 2, shall berecognized as suitable.

Suitable protective groups for the hydroxy or mercapto groups includeany of the conventional protective groups for hydroxy or mercapto groupssuch as the acyl groups which can be easily split off (e.g.benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,3,4-dimethoxybenzyloxycarbonyl, 4-phenylazobenzyloxycarbonyl,4-(4-methoxyphenylazo)benzyloxycarbonyl, tert-butoxycarbonyl,1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, 1-adamantyloxycarbonyl,1-cyclopropylethoxycarbonyl, 8-quinolylethoxycarbonyl,2,2,2-trichloroethoxycarbonyl, 3-iodopropoxycarbonyl,2-furfuryloxycarbonyl, 8-quinolyloxycarbonyl and trifluoroacetyl) andthose protecting groups other than acyl groups which can be easily splitoff, such as benzyl, trityl, methoxymethyl, 2-nitrophenylthio and2,4-dinitrophenylthio. Other conventional hydroxy and mercaptoprotecting groups, including those described in "Protective Groups inOrganic Chemistry", supra, Chapters 3 and 7, shall be considered assuitable.

The protective group for the carboxy group may be any of thoseconventional protective groups used for protecting a carboxy group, e.g.an ester group such as methyl, ethyl, propyl, isopropyl, tert-butyl,butyl, benzyl, diphenylmethyl, triphenylmethyl, p-nitrobenzyl,p-methoxybenzyl, benzoylmethyl, acetylmethyl, p-nitrobenzoylmethyl,p-chlorobenzoylmethyl, p-methanesulfonylbenzoylmethyl,phthalimidomethyl, trichloroethyl, 1,1-dimethyl-2-propynyl,acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl,1,1-dimethylpropyl, 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl,succinimidomethyl, 1-cyclopropylethyl,3,5-di(tert)butyl-4-hydroxybenzyl, methylsulfenylmethyl,phenylsulfenylmethyl, methylthiomethyl, phenylthiomethyl,dimethylaminomethyl, 2-methoxquinoline-1-oxide,2-methylpyridine-1-oxide, chlorooxalyl or di(p-methoxyphenyl)methylester, the silyl ester groups derived from a silyl compound such asdimethyldichlorosilane (which have been reported in U.S. Pat. No.3,944,545, in Japanese Patent Application No. 7332/1971 laid open topublic inspection under No. 7073/1971 and in Netherlands PatentApplication laid open to public inspection under No. 7,105,259), andmetallic or non-metallic derivatives of the carboxy group derived fromsuch compounds as boron trichloride, (C₂ H₅)₂ AlCl, (CH₃ O)₂ PCl and thelike which have been disclosed in U.K. Pat. No. 1,409,415. Other knownconventional carboxyl protecting groups such as those described in"Protective Groups in Organic Chemistry", supra, Chapter 5, shall berecognized as suitable.

In compound I, above, --COOR⁴ is defined as a protected carboxyl groupor a derivative of a carboxyl group. Suitable carboxyl-protecting groupsare well known in the art, and include those listed above for protectingcarboxyl substituents on the acyl side-chain. R⁴ also may be a metallicor non-metallic derivative such as described above for protectingcarboxyl substitutents. The group --COOR⁴ preferably is

(1) an ester: a silyl ester such as referred to above, an alkyl oralkenyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl,cyclohexyl, cycloheptyl, vinyl, 1-propenyl, 2-propenyl or 3-butenyl)ester, aryl (e.g., phenyl xylyl, tolyl or naphthyl) ester, aralkyl(e.g., benzyl or diphenylmethyl) ester, or an ester wherein one of thecarbon atoms of the alkyl group is replaced with a nitrogen, sulphur oroxygen atom, or by a carbonyl group, such as methoxymethyl ester,ethoxymethyl ester, methylthioethyl ester, methylthiomethyl ester,dimethylaminoethyl ester, diethylaminoethyl ester, phenoxymethyl ester,phenylthiomethyl ester, methylsulfenylmethyl ester, phenylsulfenylmethylester, benzoylmethyl ester or toluoylmethyl ester, or an estercontaining one or more appropriate substituents (e.g., halogen, alkoxy,alkanesulfonyl or phenylazo) such as chloromethyl ester, bromomethylester, trichloroethyl ester, cyanomethyl ester, p-nitrophenyl ester,2,4,5-trichlorophenyl ester, 2,4,6-trichlorophenyl ester,pentachlorophenyl ester, p-methylsulfonylphenyl ester, 4-phenylazophenylester, 2,4-dinitrophenyl ester, p-chlorobenzyl ester, o-nitrobenzylester, p-methoxybenzyl ester, p-nitrobenzyl ester,3,4,5-trimethoxybenzyl ester, bis(p-methoxyphenyl)methyl ester,pentachlorobenzyl ester, trichlorobenzyl ester,3,5-di(tert)butyl-4-hydroxybenzyl ester, p-nitrophenylthiomethyl ester,p-nitrobenzoylmethyl ester or p-chlorobenzoylmethyl ester, or an esterformed from a thioalcohol, a substituted thioalcohol,N-hydroxysuccinimide, N-hydroxyphthalimide, tetrahydrofuran,1-cyclopropylethanol, 1-phenyl-3-methyl-5-pyrazolone, 3-hydroxypyridine,2-hydroxymethylpyridine-1-oxide, 1-hydroxy-2(1H)-pyridine,dimethylhydroxyamine, diethylhydroxyamine, glycolamide,8-hydroxyquinoline, 2-hydroxymethylquinoline-1-oxide, methoxyacetylene,ethoxyacetylene, tert-butylethynyldimethylamine,tert-butylethynyldiethylamine, ethylethynyldiethylamine or2-ethyl-5-(3-sulfophenyl)isoxazolium hydroxide inner salt; or

(2) an acid amide: an N-alkyl amide (e.g., N-methyl acid amide orN-ethyl acid amide), N,N-dialkyl acid amide (e.g., N,N-dimethyl acidamide, N,N-diethyl acid amide or N-methyl-N-ethyl acid amide), or anacid amide with imidazole, benzotriazole, a 4-substituted imidazole or aprotected tetrazole.

Other known conventional carboxy protecting groups such as thosedescribed in "Protective Groups in Organic Chemistry", supra, Chapter 5,shall be recognized as suitable.

The reaction of the penicillin sulfoxide (I) with the isocyanate (II) isconducted in an inert organic solvent such as dioxane, toluene, xylene,benzene, tetrahydrofuran, methyl isobutyl ketone, 1,2-dichloroethane,methyl chloroform or the like. The reaction may, if desired, beconducted in excess isocyanate as the solvent. Dioxane is a preferredsolvent.

The reaction may be conducted over a wide temperature range, e.g. up toabout 200°, preferably from about 70° to about 140° and most preferablyfrom about 90° to about 115°. It is most convenient to conduct thereaction at the reflux temperature of a suitably selected solvent.

The reaction time is not critical and may range from 1 hour to 24 hours,or more, depending on the particular reactants, reaction temperature,etc.. In general, we prefer to conduct the reaction for from about 1 toabout 10 hours, and typically from about 3 to about 7 hours.

The penicillin sulfoxide (I) is reacted with at least one equivalent ofthe isocyanate (II) and preferably with an excess thereof. Up to about 5equivalents, or more, of isocyanate may be utilized, but no advantage isobtained by using greater amounts. The isocyanate aids in maintaining ananhydrous reaction medium by scavenging any free water which may bepresent. We prefer to use from about 2 to 4 equivalents of theisocyanate, and most preferably about 3 equivalents of the isocyanate,per equivalent of the penicillin sulfoxide.

If the reaction of the penicillin sulfoxide (I) and the isocyanate (II)is conducted in the absence of a base the product is primarily a mixtureof the penam (III) and the cepham (IV), along with a small amount of thecephem (V). The ratio of the penam and cepham in the product may bevaried by the use of different isocyanates. Thus, for example, when thep-nitrobenzyl ester of penicillin V sulfoxide is reacted in dioxane withsilicon tetraisocyanate, the product usually consists of 95-98% of thepenam and traces of the cepham. However, the reaction of thep-nitrobenzyl ester of penicillin V sulfoxide in dioxane withtrichloroacetyl isocyanate gives a product which typically is 30-35%penam, 60-65% cepham and about 5% cephem. The product mixture mayreadily be separated into its components by chromatography, e.g. onsilica gel.

Penam (III) and/or cephem (IV) may be converted to cepham (V) bytreatment with base, as shown in the general reaction scheme, above.Alternatively, if the cephem (V) is the desired product, the penicillinsulfoxide (I) may be reacted with the isocyanate (II) in the presence ofa base to give the cephem (V) directly. When preparing the cephemdirectly in this manner, we have found that highest yields of the cephemare obtained if a source of bromide ions is also added to the reactionmixture.

When converting penam (III) and/or cepham (IV) to cephem (V) bytreatment with base, one may use any organic or inorganic base. Thereaction may be conducted in an organic solvent by using a base which issoluble therein or by using a two-phase aqueous-organic solvent systemwherein the base is water soluble.

When utilizing a two-phase system for base treatment of the penam and/orcepham, one may utilize any of the usual water-soluble bases, e.g. NaOH,KOH, K₂ CO₃, Na₂ CO₃, NaHCO₃, KHCO₃, an alkaline phosphate buffer, orthe like. When the base treatment is conducted in an organic solvent,one may use any of the usual organic-soluble bases, e.g. a tertiaryamine such as triethylamine, pyridine, quinoline, isoquinoline,lutidine, tetramethylguanidine, or the like. We have found that somebases such as K₂ CO₃, which are generally considered to be insoluble inorganic solvents, appear to have sufficient solubility in certainorganic solvents such as dioxane to be utilized in such systems.

Thus, the penam (III) and/or cepham (IV) (either as isolated products oras the crude reaction mixture) may be converted to the correspondingcephem (V) by adjusting a solution thereof to an alkaline pH andmaintaining it at an alkaline pH for from about 15 minutes to 24 hours,depending on the temperature, base, particular reactants and solventsystem. The temperature is not critical. We find that 0°-40° is aconvenient range and that 0°-25° is preferred. Higher temperatures maybe used but normally decrease the yield of desired product, while lowertemperatures require excessively long reaction times.

The base utilized to convert the penam and/or cepham to the cepham neednot be added in a stoichiometric amount, as this is merely a catalyst.We have utilized from about 5 to about 150 mole percent of base andprefer to use from about 20 to about 50 mole percent. A greater amountof base may be utilized but normally does not increase the yield. Theuse of less than about 5 mole percent of base usually unduly increasesthe reaction time and/or yield of product. The most suitable amount ofbase depends on the particular penam and/or cepham being treated, aswell as on the particular solvent system.

As indicated above, we have found that, in the "one-step" reaction of apenicillin sulfoxide with an isocyanate in the presence of a base toproduce the cephem directly, the yield of cephem is normallysignificantly increased by the addition of a source of bromide ions tothe reaction mixture. Suitable sources of bromide ion will be apparentto those skilled in the art, and include acetyl bromide, propionylbromide, benzoyl bromide, pyridine hydrobromide, trimethylbromosilane,thionyl bromide, boron tribromide, silicon tetrabromide, aluminumtribromide, tin tetrabromide, and the like. The amount of bromide givingthe best yield of cephem will depend on the particular penicillinsulfoxide, isocyanate, base and solvent being utilized. We have foundthat from about 5 to about 50 mole percent of bromide is adequate whilefrom about 10 to about 30 mole percent is usually preferred.

After reaction of the penicillin sulfoxide with the isocyanate toproduce the desired penam (III), cepham (IV) or cephem (V), the latterproducts will still contain a protected carboxyl group, i.e. R⁷ isinitially the same as R⁴. It is usually desired to remove the protectinggroup to produce the corresponding compound containing a free carboxylgroup (i.e. R⁷ is hydrogen). Removal of the carboxyl-protecting group isachieved by conventional treatment, e.g. catalytic hydrogenolysis in thecase of the p-nitrobenzyl protecting group. This may be accomplished,for example, by the use of hydrogen in the presence of a catalyst suchas palladium or rhodium on a carrier such as charcoal, barium sulfate oralumina. Alternative methods of removal of the protecting group includereaction with Lewis acids such as trifluoroacetic acid, formic acid orzinc bromide in benzene (the reaction with Lewis acids may befacilitated by the addition of a nucleophile such as anisole), or byreduction with agents such as zinc/acetic acid or zinc/formic acid, orby reaction with nucleophiles such as those containing a nucleophilicoxygen or sulfur atom, e.g. alcohols, mercaptans or water.

The side chains of penam (III), cepham (IV) and cephem (V) may, ifdesired, be cleaved to give the free 6-amino compound (penams) or7-amino compound (cephams and cephems). Cleavage may be effected bymeans of enzymes or by chemical hydrolysis or hydrogenolysis. If theside chain is to be cleaved, such cleavage preferably is conducted priorto removal of the carboxyl-protecting group. In the chemical hydrolysisof the side chain, the penam, cepham or cepham is first converted to animino halide by reaction with a halogenating agent such as phosphoruspentachloride, phosphorus oxychloride, phosgene, thionyl chloride,oxalyl chloride or p-toluenesulfonyl chloride (and preferably phosphoruspentachloride or phosphorus oxychloride) in the presence of an acidbinding agent. The reaction is conducted in an inert organic solventsuch as diethyl ether, nitromethane or a halogenated hydrocarbon(methylene chloride and chloroform are the preferred solvents). It ispreferred to use an excess of the halogenating agent (up to about 2moles per mole of penam, cepham or cephem) and to use from about 1.5 toabout 5 moles of acid binding agent per mole of halogenating agent.Suitable acid binding agents are tertiary amines such as triethylamine,N,N-dimethylaniline, pyridine, quinoline lutidine, picoline and thelike. The reaction may be conducted at a temperature of from about -60°to -10° for penams and at from about -60° to about +10° for cephams andcephems. We prefer to conduct the reaction at from about -30° to about-40°.

The imino halide prepared in the above step is then converted into animino ether by reaction with a primary or secondary alcohol in thepresence of an acid binding agent (this is usually most simplyaccomplished by conducting this step without isolation of the iminohalide). Suitable alcohols include alkanols such as methanol, ethanol,propanol, isopropanol, butanol and isobutanol; aralkanols such as benzylalcohol and 2-phenylethanol; cycloalkanols such as cyclohexanol; andalkanediols such as ethylene glycol and 1,6-hexanediol. The preferredalcohol is methanol. The reaction may be conducted over the sametemperature range as in the formation of the imino halide, andpreferably is conducted at from about -30° to about -40°.

The imino ether is then hydrolyzed to produce the free amino compound.This is most simply accomplished by quenching the solution of the iminoether with water at a temperature of from about -5° to about +10°.

Chemical cleavage of the acyl side-chain, such as described above, alsowill remove some or all of the substituent R⁶ on the penam and cepham,depending on the particular nature of R⁶, the particular halogenatingagent which is utilized, the temperature at which the reaction isconducted, the particular work-up procedure, etc. Thus, with the penamhaving a phenoxyacetamido side-chain and R⁶ substituent which istrichloroacetyl, PCl₅ mediated cleavage followed by work-up in methanolwith a bicarbonate will remove both groups. In such cases (where twoacyl groups are being removed) one should utilize about twice the amountof halogenating agent and alcohol referred to above. In those caseswhere little or no R⁶ group is removed during side-chain cleavage, theamount of halogenating agent and alcohol should be in the range statedabove. It will be appreciated by those skilled in the art that PCl₅side-chain cleavage cannot be utilized on compounds III or IV wherein R⁶is hydrogen, since the free carbamoyl group will be destroyed. Theside-chain may be removed without removing substituent R⁶ of the penamor cepham (wherein R⁶ is other than hydrogen) by utilizing specifichalogenating agents and specific R⁶ substituents. Similarly, one mayremove the R⁶ substituent of the penam or cepham without removing theside-chain by utilizing suitable R⁶ substituents and methods of removal,e.g. if R⁶ is chloroacetyl, it may be removed with thiourea, withoutremoving the side-chain. The trichloroacetyl group may be removed by theuse of sodium bicarbonate in methanol.

Cleavage of the 6- or 7-acyl side-chain in the penam (III) or cepham(IV) may be achieved by hydrogenolysis techniques when the side-chain isa group readily removed by such techniques, e.g.p-nitrobenzyloxycarbonyl.

When a penicillin sulfoxide ester of Formula I is reacted with anisocyanate of Formula II in which n=1 (i.e. a monoisocyanate), R⁶ in theresulting penam (III) or cepham (IV) will be the same as R⁵. If,however, n is greater than 1 (i.e. is 2-4), then the resulting R⁶substituent on the penam or cepham may have the structure XII shownabove. Thus, if a penicillin sulfoxide ester is reacted with, forexample, carbonyl diisocyanate, the initially resulting product will bea carbonyl group which is substituted with two penam moieties, with twocepham moieties, or with one penam moiety and 1 cepham moiety, or amixture of these products. Such bis-, tris- and tetrakis-penam or cephamcompounds may be utilized in that form (after removal of the carboxylprotecting groups) or they may be split to the mono-substitutedcompounds either under normal workup steps or by subsequent procedures.

After cleavage of the side-chains from the penam (III), cepham (IV) orcephem (V) to produce the free amino compounds of Formula VI, VII orVIII, the latter compounds may be reacylated with a different side-chainto produce compounds of Formula IX, X or XI. Briefly, a compound ofFormula VI, VII or VIII is reacted with an acid of the formula ##STR38##or with an acylating derivative of said acid, in which ##STR39## is aconventional acyl group known in the penicillin or cephalosporin art.Such conventional acyl groups include, but are not limited to, thoseexemplified above for R².

In the acylation of a compound of Formula VI, VII or VIII, thecarboxylic acid of formula XIII may be used per se in which case it ispreferred to use an enzyme or a condensing agent. Suitable condensingagents include, N,N-dimethylchloroformiminium chloride, anN,N'-carbonyldiimidazole or an N,N'-carbonylditriazole, a carbodiimidereagent [especially N,N'-dicyclohexylcarbodiimide,N,N'-diisopropylcarbodiimide orN-cyclohexyl-N'-(2-morpholinoethyl)carbodiimide], an alkynylaminereagent, isoxazolium salt reagent, ketenimine reagent,hexachlorocyclotriphosphatriazine or hexabromocyclotriphosphatriazine,diphenylphosphoryl azide (DPPA), diethylphosphosphorylcyanide (DEPC),diphenylphosphite or N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline(EEDQ).

As an alternative to using the carboxylic acid XIII in the aboveprocess, there may also be employed reactive acylating derivatives ofacid XIII, i.e. functional equivalents of the acid as acylating agentsfor a primary amino group. Examples of reactive acylating derivatives ofthe carboxylic acid include the acid halide (e.g. acid chloride or acidbromide), acid anhydrides, including mixed anhydrides (e.g. alkoxyformicanhydrides), acid azides, active esters (e.g. p-nitrophenyl) and activethioesters. Another reactive derivative of the acid is a correspondingazolide, i.e. an amide of the acid whose amide nitrogen is a member of aquasiaromatic five-membered ring containing at least two nitrogen atoms,i.e. imidazole, pyrazole, the triazoles, benzimidazole, benzotriazoleand their substituted derivatives. The general method for preparation ofazolides is described, for example, in U.S. Pat. No. 3,910,900.

Mention was made above of the use of enzymes to couple the free acidwith a compound of Formula VI, VII or VIII. Included in the scope ofsuch processes are the use of an ester, e.g. the methyl ester, of thatfree acid with enzymes provided by various microorganisms, e.g. thosedescribed in J. Am. Chem. Soc., 94(11), 4035-4037 (1972), J. Antibiotics(Japan), 24(5), 321-323 (1971) and U.S. Pat. No. 3,682,777.

The acylation process is conducted in a reaction-inert solvent systemwhich can be aqueous or non-aqueous. Suitable reaction-inert solventsinclude, for example, water, acetone, tetrahydrofuran, dioxane,acetonitrile, dimethylformamide, dimethylsulfoxide, methylene chloride,chloroform, benzene, toluene, methyl isobutyl ketone and mixtures of theabove-mentioned organic solvents with water. The choice of solvent, i.e.particularly whether an aqueous or non-aqueous solvent is used, isdependent on the particular starting materials employed. Thus, forexample, if the starting compound of Formula VI, VII or VIII is used inthe form where the 3- or 4-carboxyl moiety is protected by an estergroup cleaved by hydroxylic solvents, e.g. a silyl or stannyl ester, anaprotic organic solvent is most preferably employed. When the startingcompound of Formula VI, VII or VIII is used in its salt form, water oran aqueous organic solvent system is preferably employed. The mostadvantageous solvent system for the particular reagents used can bedetermined by routine experimentation.

The duration and temperature of the acylation reaction are not critical.Temperatures in the range of from about -30° C. to about +50° C. arecommonly used for reaction times ranging from less than one hour up to aday or more. Although the initial contacting of the reactants ispreferably carried out at around 0° C. to reduce the incident ofby-products, it is frequently desirable after a few minutes of mixing toallow the reaction mixture to warm to room temperature until thereaction is complete.

Any of compounds III-XI of this invention, after removal of thecarboxyl-protecting group R⁷, may be converted, if desired, to apharmaceutically acceptable salt or to a physiologically hydrolyzedester such as the pivaloyloxymethyl, acetoxymethyl, phthalidyl,5-indanyl or methoxymethyl ester.

As shown by the wavy lines in the structural formula for Compound I, thesubstituents on the 6-position may have either stereochemicalconfiguration, i.e. the amino moiety may have the normal β configurationand R³ the normal α configuration, or these may be reversed. Whateverthe configuration at the 6-position of starting Compound I, the sameconfiguration will be maintained in the penam, cepham or cephem product.

However, the configuration of the 2-position of penam III or the3-position of cepham IV is dependent on the configuration of thesulfoxide moiety of starting Compound I. Thus, as shown in the followingequations, the S sulfoxide (Ia) gives primarily the R penam (IIIa) or Scepham (IVa), while the R sulfoxide (Ib) gives primarily the S penam(IIIb) or the R cepham (IVb), which readily eliminates to the cephem.##STR40## Depending on the particular substituent groups on the startingpenicillin sulfoxide, small to moderate amounts of the product havingthe alternate configuration may also be produced.

The reaction of penicillin sulfoxides of Formula I with isocyanates ofFormula II to produce the penams of Formula III and/or the ring-expandedcephams and cephems of Formulae IV and V, respectively, is completelyunprecedented. The literature indicates that sulfoxides react withactivated isocyanates such as acyl isocyanates to produce sulfilimines.The literature also indicates that activated isocyanates such as acylisocyanates react with amides to give acyl ureas and amidines (see, forexample, H. Ulrich, Chemical Reviews, 65, 369 (1965)). It wouldtherefore be expected that penicillin sulfoxides would give suchunwanted products upon reaction with activated isocyanates such as thosedescribed herein, particularly at elevated temperatures. To oursurprise, we have found that acyl isocyanates and other activatedisocyanates of Formula II, above, react with penicillin sulfoxides (inwhich the carboxyl group is blocked) to give the new2-carbamoyloxymethylpenams of Formula III and 3-carbamoyloxycephams ofFormula IV, as well as the corresponding 3-methyl-Δ³ -cephems of FormulaV.

In terms of the ring-expansion aspect of the present invention, the useof isocyanates of Formula II offer several advantages over presentlyknown ring expansion processes, e.g.

(1) Isocyanates of Formula II maintain an anhydrous situation throughoutthe ring expansion reaction, thus avoiding the water-induced degradationreactions which can occur in catalytic ring expansion processes.

(2) Ring expansion utilizing isocyanates of Formula II are faster thancatalytic ring expansion processes.

(3) Isocyanates of Formula II are twice as effective in scavengingactive hydrogen compounds than the trimethylsilyl compounds used in someother processes. Thus, one molecule of water is scavenged by oneisocyanate group or by two trimethylsilyl groups.

(4) Isocyanates such as acetyl isocyanate, methanesulfonyl isocyanate,sulfonyl diisocyanate, carbonyl diisocyanate and phosphoroustriisocyanate give, as reaction by-proucts, acetamide+CO₂,methanesulfonamide+CO₂, sulfonamide+CO₂, urea+CO₂ and phosphorousamides+CO₂, respectively. These are simpler to handle and dispose ofthan by-products from processes utilizing bistrimethylsilyl urea, i.e.urea+hexamethyldisiloxane. Further, such neutral amide by-products do noreact with the lactam ring.

(5) Many of the isocyanates of Formula II are substantially lessexpensive than bistrimethylsilyl urea and other trimethylsilyl ureasutilized in other ring expansion processes.

(6) Many of the isocyanates of Formula II are liquids at roomtemperature. From a practical plant point of view, liquids are easier,and generally safer and less costly to dispense and handle than solids.Most of the silyl compounds utilized in other ring-expansion processesare solids.

(7) From a practical point of view, isocyanates of Formula II may beselected such that their by-products are easily separated from thedesired product by different techniques. For example, acyl isocyanatesgive water-soluble amides as by-products. Silicon tetraisocyanate, onthe other hand, gives silica as a by-product, which is completelyinsoluble in either organic or aqueous solvents.

The starting compounds for use in the present process are either known(many are commercially available) or may be prepared by known proceduresfrom readily available materials. Many of the penicillin sulfoxides ofFormula I are known; others may be prepared from the correspondingpenicillin by standard techniques well known to those skilled in theart, e.g. by use of sodium metaperiodate, hydrogen peroxide in aceticacid, m-chloroperbenzoic acid, iodobenzene dichloride in aqueouspyridine, ozone, or aqueous bromine. The penicillins themselves also areeither known or may be prepared by acylating 6-aminopenicillanic acidwith the appropriate side-chain acid, using standard procedures known inthe art.

The isocyanates of Formula II also are known or are readily prepared byknown techniques from available starting materials. Thus, acetylisocyanate and similar isocyanates may be prepared by the proceduredescribed in Berichte, 36, 3213 (1903); the preparation of chloroacetylisocyanate is described in J. Org. Chem., 27, 3742 (1962); thepreparation of silicon tetraisocyanate is described in InorganicSyntheses, 8, 27 (1966); the preparation of sulfonyl diisocyanate isdescribed in W. German Pat. Nos. 940,351 and 1,150,093; and thepreparation of methylsulfonyl isocyanate is described in J. Org. Chem.,39, 1597 (1974). General procedures for the preparation of many sulfonylisocyanates are given in Chemical Reviews, 65, 369 (1965) and referencescited therein.

The penams of Formulae III and IX, the cephams of Formulae IV and X, andthe cephems of Formulae V and XI provided by the present invention(after removal of the carboxyl-protecting group to produce the freeacid) are active against various Gram-positive and Gram-negativeorganisms and, accordingly, are useful antibacterial agents for thetreatment of diseases caused by such organisms in animals, includingman.

The free-amino compounds of Formulae VI, VII and VIII obtained byside-chain cleavage of the compounds of Formulae III, IV and V,respectively, generally have lower antibacterial activity than compoundsIII-IV or IX-XI. Although they may sometimes be utilizedtherapeutically, their primary utility is as intermediates in thepreparation of compounds of Formulae IX-XI by re-acylation of the freeamino group.

The antibacterial compounds provided by the present invention may beused alone or as the (or an) active ingredient in a conventionalpharmaceutical composition, by analogy with other penicillins andcephalosporins. They may be administered orally, parenterally or bysuppository. For oral administration the compositions may be in the formof tablets, capsules, powders, granules, lozenges, solutions orsuspensions. They may contain conventional excipients suitable to thedosage form, e.g. binding agents, fillers, lubricants, disintegratingagents, wetting agents, stabilizers, sweetening agents, flavors, and thelike. Suppositories will contain conventional suppository bases. Forparenteral administration, one may utilize fluid unit dosage forms suchas sterile solutions or suspensions, or sterile powders intended forreconstitution with a sterile vehicle prior to administration.Conventional adjuvants such as preservatives, buffering agents,suspending agents, and the like may be included in parenteralcompositions.

The compositions may contain from 0.1% to 99% by weight of theantibacterial compounds of the present invention. When the compositionsare in unit dosage form, each unit will contain from about 100-750 mg ofthe active ingredient. They are administered in an amount of from about15 to about 250 mg/kg/day in divided doses, e.g. 3 to 4 times per day.

It will be appreciated by those skilled in the art that the penams (IIIand IX), cephams (IV and X) and cephems (V and XI) provided by thepresent invention potentially contain an asymmetric carbon atom in theirside-chain. It is specifically intended that this invention include allpossible epimers, as well as mixtures thereof.

The Minimum Inhibitory Concentrations (MIC's) of some of the compoundsof this invention were determined against a number of organisms, and theresults are shown in Table 1. The substituents "R" and "X" in Table 1refer to the stated substituents on the following skeletal structure

This invention is illustrated by, but in no way limited to, the specificExamples.

                                      TABLE 1                                     __________________________________________________________________________                     Organism                                                                      Minimum Inhibitory Concentration (μg/ml)                                                        S. aureus                                                                            S. aureus                                         S. pneumoniae                                                                         S. pyogenes                                                                          S. aureus                                                                           A-9537 A-9606                           Compound         A-9585  A-9604 A-9537                                                                              +50% serum                                                                           (pen resist)                     __________________________________________________________________________    R = C.sub.6 H.sub.5 OCH.sub.2 CONH                                             ##STR42##       0.06    --     0.25  2      >125                             R = C.sub.6 H.sub.5 OCH.sub.2 CONH                                             ##STR43##       0.016   0.008  0.06  0.06   >125                              ##STR44##                                                                     ##STR45##       0.13    0.25   2     8      4                                 ##STR46##                                                                     ##STR47##       0.03    0.06   >1    8      4                                 ##STR48##                                                                     ##STR49##       0.25    --     2     32     4                                 ##STR50##                                                                     ##STR51##       0.5     0.5    2     16     4                                 ##STR52##                                                                     ##STR53##       0.13    0.13   2     2      >125                              ##STR54##                                                                     ##STR55##       0.5     0.5    4     16     4                                R = C.sub.6 H.sub.5 CH.sub.2 CONH                                              ##STR56##       0.06    --     0.5   1      >125                             R = C.sub.6 H.sub.5 OCH.sub.2 CONH                                             ##STR57##       4       --     >8    >63    125                              R = H.sub.2 N    31 > -                                                                         ##STR58##                                                                            16     32    >125   >63 >125                         R = H.sub.2 N                                                                  ##STR59##       1       4      >125  >63    >125                             __________________________________________________________________________

EXAMPLE 1 (A) (2R,3S,5R,6R)2-(N-Acetyl)carbamoyloxymethyl-2-methyl-6-phenoxyacetamidopenam-3-carboxylicAcid p-Nitrobenzyl Ester

A solution of (1S,3S,5R,6R)2,2-dimethyl-6-phenoxyacetamidopenam-3-carboxylic acid-1-oxidep-nitrobenzyl ester (25.18 g, 50.0 mmol), acetyl isocyanate (8.50 ml,9.53 g, 112 mmol), and dioxane (250 ml) was refluxed under nitrogen for5 hours, cooled and concentrated in vacuo to a yellow foam. The foam waschromatographed on silica gel (1.7 Kg) with methylene chloride: acetone;9:1; v:v to give four products; the 3-methyl-Δ³ -cephem; startingsulfoxide, the title penam, and the cepham (in order of elution). Thepenam fractions were concentrated to a colorless foam in 40.2% yield(11.80 g). Re-chromatography of a portion gave an analytical sample:m.p. 83°-85°; nmr 100 MHz (CDCl₃) ppm 8.40 ##STR60## 8.20 (2, d, J=8.5,1/2 aromatic AB pNB), 7.56 (3, d, J=8.5 over m, 1/2 AB, pNB and C₆--NH), 7.5 (2, m) and 6.9 (3, m, O--Ph--H's), 5.7 (2, m's, C₅ --C₆--H's), 5.32 (2, br s, pNB methylene), 4.88 (1, s, C₃ --H), 4.56##STR61## 4.26 and 4.06 (2, d's, J=11.5, AB of C₂ --CH₂ O), 2.22##STR62## and 1.47 (3, s, C₂ --CH₃); nmr ¹³ C 4 carbonyls ca 170 ppm,carbamate carbonyl C 157.0, C₂ singlet at 67.4, while C₂ --CH₂ O is t at72.3, and C₂ --CH₃ is q at 21.7.

Anal. Calc'd for C₂₆ H₂₆ N₄ O₁₀ S: C, 53.23; H, 4.47; N, 9.55. Found: C,53.21; H, 4.49; N, 9.39.

(B) (3S,4R,5R,6R)3-(N-acetyl)carbamoyloxy-3-methyl-7-phenoxyacetamidocepham-4-carboxylicacid p-nitrobenzyl ester

The final chromatographic band from Step A, above, was concentrated invacuo to give the title cepham in 12.4% yield (3.66 g): nmr (CDCl₃) 100MHz ppm 9.89 ##STR63## 8.23 (2, d, J=8.2 Hz, 1/2 pNB AB), 7.56 (2, d,J=8.2, 1/2 pNB AB) 7.24 (2, m) and 6.9 (3, m, OPh--H's), 5.55 (1, dd,J=9.5, 4.0, C₇ --H), 5.32 (3, br s over m, pNB--CH₂ and C₆ --H), 4.94(1, s, C₄ --H), 4.52 ##STR64## 3.56 and 3.34 (2, 2 d's, J=15.5, C₂ --H₂AB), 2.27 ##STR65## and 1.60 (3, s, C₄ --CH₃); ¹³ C 4 carbonyls ca 170ppm carbamate carbonyl C 157.0, C₂ (t, 29.5), C₃ (s, 74.3), C₄ --CH₃ (q,21.7).

EXAMPLE 2 (2R,3S,5R,6R)2-(N-Acetyl)carbamoyloxymethyl-2-methyl-6-phenoxyacetamidopenam-3-carboxylicAcid

A suspension of 10% palladium on charcoal (400 mg) in ethyl acetate (40ml) and aqueous 0.5% sodium bicarbonate was prehydrogenated and chargedwith (2R,3S,5R,6R)2-(N-acetyl)carbamoyloxymethyl-2-methyl-6-phenoxyacetamidopenam-3-carboxylicacid p-nitrobenzyl ester (400 mg 0.68 mmol). The whole was shaken at 50psi hydrogen pressure for 30 minutes and polish filtered. The aqueouswas washed with ethyl acetate (20 ml), combined with a back extract ofH₂ O (20 ml), overlayed with ethyl acetate (25 ml) and adjusted to pH2.9 with 35% sulfuric acid. The layers were separated and the richorganic phase was washed with water (20 ml), combined with a backextract (EtOAc, 20 ml), dried (4A sieves), polish filtered andconcentrated in vacuo to a colorless foam (270 mg) in 87% yield: nmr 100MHz (CDCl₃ --D₂ O) ppm 7.32 (2, m, m-phenyl H's) 6.96 (3, m, o,p-phenylH's), 5.59 (2, br s, mag. equiv. C₅,C₆ --H's), 4.79 (1, s, C₃ --H), 4.59##STR66## 4.08 (m, AB of C₂ --CH₂ O), 2.25 ##STR67## and 1.58 (3, s, C₃--Me) with small ethyl acetate impurity.

EXAMPLE 3 (2R,3S,5R,6R) p-Nitrobenzyl2-(N-Chloroacetyl)carbamoyloxymethyl-2-methyl-6-(2-phenoxyacetamido)penam-3-carboxylate

A solution of (1S,3S,5R,6R)2,2-dimethyl-6-phenoxyacetamidopenam-3-carboxylic acid-1-oxidep-nitrobenzyl ester (5.01 g, 10.0 mmol) and chloroacetyl isocyanate (5.0g, 40 mmol) in dioxane (50 ml) was heated at reflux under nitrogen for 4hours. The solution was concentrated in vacuo and crudely separated byfiltration through silica gel (75 g) with methylene chloride:acetone(9:1 v/v). The filtrate was concentrated and chromatographed on silicagel (140 g) with the same solvent. The second of three product bands(cephem, penam, and cepham) was concentrated in vacuo to crude product(0.53 g) a portion of which (0.23 g) was crystallized from hot methanol(5 ml, Darco) to return the title compound as a colorless solid (0.11g): nmr (CDCl₃, 100 MHz) ppm 8.46 ##STR68## 8.21 (d, 2, J=13.2 Hz, 1/2aromatic AB p-NO₂ benzyl), 7.4 (overlapping m's, 5, 1/2 AB, acyl NH, andorthophenoxy), 6.95 (m's, 3, m,p-phenoxyl), 5.7 (overlapping m's, 2,C₅,C₆ --H's), 5.30 (s, 2, benzyl-CH₂), 4.81 (s, 1, C₃ --H), 4.54 (s, 2,phenoxyacetyl CH₂); 4.25 (overlapping AB m's, 4, ClCH₂ and C₂ --CH₂ O),and 1.45 (s, 3, CH₃); ¹³ C nmr consistent with four carbonyls ca 170 ppmand carbamate carbonyl at 157.2 ppm.

EXAMPLE 4 (A) (2R,3S,5R,6R)2-carbamoyloxymethyl-2-methyl-6-(2-ethoxynaphthoylamido)penam-3-carboxylicAcid p-Nitrobenzyl Ester

A solution of trichloroacetyl isocyanate (4.2 ml, 6.6 g, 35 mmol),(1S,3S,5R,6R) 2,2-dimethyl-6-(2-ethoxynaphthoylamido)penam-3-carboxylicacid-1-oxide p-nitrobenzyl ester (7.35 g, 12.5 mmol), and dioxane (65ml) was refluxed under nitrogen for 3.5 hours and concentrated in vacuoto an oil. The oil was taken into methanol (125 ml), the solution wasadjusted to pH 7.4 with 5% sodium bicarbonate, and the mixture was heldat pH 7.4 to 7.5 with 3% H₂ SO₄ for 2 hours. A precipitate was removedby filtration with a methanol wash (20 ml), and the filtrate wasdistributed between methylene chloride (250 ml) and water (80 ml). Theorganic layer was washed with water (75 ml), combined with aback-extract (CHCl₂, 75 ml), dried (4A sieve), polish filtered, andconcentrated in vacuo.

The concentrate was chromatographed on silica gel (500 g) with CH₂ Cl₂:acetone, 9:1, v:v to give three major products; the Δ³ cephem, thetitle penam, and the cepham (see below). The middle fractions wereconcentrated to a very pale yellow foam (1.49 g) 19.6%:

nmr 100 MHz (CDCl₃) ppm 8.41 (2, d, J=9 Hz, 1/2 aromatic AB pNB),8.0-7.1 (9, aromatics +NH), 6.08 (1, dd, J=4.2, 9, C₆ --H), 5.74 (1, d,J=4.2, C₅ --H), 5.36 and 5.21 (2, d's, J=13, AB pNB methylene), 4.73 (1,s, C₃ --H), 4.60 (2, br s, NH₂), 4.21 (q, J=7) with 4.12 (d, J=11.5,total 3, OCH₂ CH₃ and C₂ --CHHO--), 3.84 (1, d, J=11.5, C₂ --CHHO), and1.40 (t, J=7) with 1.38 (s, total 6, CH₂ CH₃ and C₂ --CH₃).

(B) (3S,4R,5R,6R)-3-Carbamoyloxy-3-methyl-7-(2-ethoxynaphthoylamido)cepham-4-carboxylic Acid p-NitrobenzylEster

The last major product fractions of Step A, above, were concentrated invacuo to give the title product as a light yellow foam (2.6%, 0.20 g);nmr CDCl₃ 80 MHz ppm 8.5-6.9 (7, m's, aromatics and C₇ --NH), 5.96 (1,dd, J=9.3, 4.5 Hz, C₇ --H), 5.44 (1, d, J=4.5, C₆ --H), 4.21 (2, s, pNBCH₂), 4.87 (1, s, C₄ --H), 4.71 (2, br s, --NH₂), 4.24 (2, q, J=7.0, CH₂--CH₃), 3.54 (1, br d, J=14.6, 1/2 C₂ AB), 3.28 (1, d, J=14.6, 1/2 C₂AB), and 1.48 (s, C₃ --CH₃) with 1.44 (t, J=7.0, total 6).

EXAMPLE 5 (2R,3S,5R,6R)2-carbamoyloxymethyl-2-methyl-6-(2-ethoxynaphthoylamido)penam-3-carboxylicAcid

The p-nitrobenzyl ester of the title compound (610 mg, 1.0 mmol) wasadded to a prehydrogenated suspension of 10% palladium on carbon inethyl acetate (25 ml) and aqueous potassium bicarbonate (0.4%, 20 ml).The whole was shaken at 50 psi hydrogen pressure for 60 minutes, andcentrifuged. The organic phase and the solids were extracted with 0.2%KHCO₃ (2×20 ml) and the combined aqueous phase was washed with methylenechloride (20 ml). The aqueous phase was stirred with fresh CH₂ Cl₂ (25ml) during pH adjustment to 2.0 with 35% sulfuric acid and the layerswere separated. The rich organic phase was washed with pH 2 buffer (15ml), combined with a back extract (CH₂ Cl₂, 25 ml), dried (4A sieves),polish filtered, and concentrated in vacuo to a green-tinted foam (170mg) 36%: nmr 100 MHz (CDCl₃) ppm 8.1-7.1 (8, 3 m's aromatics+C₆ --NH,exchangeable near 7.9), 5.98 (1, dd, J=4, 8.5 Hz, C₆ --H), 5.75 (1, d,J=4, C₅ --H), 5.54 (2, br s, exchangeable, NH₂), 4.62 (1, s, C₃ --H),4.23 (q, J=7) and 4.19 (d, J=11.5, 3 total, OCH₂ CH₃ and 1/2 CHHO AB),3.86 (1, d, J=11.5, 1/2 CHHO), and 1.57 (s) with 1.44 (t, J=7, total 6,C₂ --CH₃ and CH₂ --CH₃).

EXAMPLE 6 (2R,3S,5R,6R)2-Carbamoyloxymethyl-2-methyl-6-(2-phenoxyacetamido)penam-3-carboxylicAcid p-Nitrobenzyl Ester

A solution of (1S,3S,5R,6R)2,2-dimethyl-6-phenoxyacetamidopenam-3-carboxylic acid-1-oxidep-nitrobenzyl ester (7.52 g, 15.0 mmol) and trichloroacetyl isocyanate(5.0 ml, 7.9 g, 42 mmol) in dioxane (75 ml) was refluxed under nitrogenfor 3.5 hours and concentrated in vacuo. The concentrate was stirredwith methanol (100 ml) and the solution was decanted from a black tarwith methanol rinses (2×10 ml). The solution was diluted with water (5ml), adjusted to pH 7.4 with 5% sodium bicarbonate, and held at pH7.4-7.5 with 3% H₂ SO₄ for 2.5 hours. The mixture was distributedbetween methylene chloride (100 ml) and water (50 ml). The organic phasewas washed with water (50 ml), combined with a CH₂ Cl₂ back extract (50ml), dried (4A molecular sieve), polish filtered with CH₂ Cl₂ washes(2×20 ml), and concentrated in vacuo to a light brown oil.

The oil was chromatographed on silica gel (500 g) with methylenechloride:acetone, (9:1; v:v) to give the title product, as the second oftwo major zones, concentrated in vacuo to a pale yellow foam (2.01 g)25%; identical by nmr and tlc to the analytical sample prepared by asecond chromatography and concentration to a colorless foam: mp 76°d;nmr (CDCl₃) 100 MHz ppm 8.22 (2, d, J=9 Hz, 1/2aromatic AB pNB), 7.52overlapping 6.8-7.7 (8, d, J=9, 1/2pNB, with m's phenoxy H's, NH), 5.75(dd, J=4, 9 C₆ --H) with 5.63 (d, J=4, total 2, C₅ --H), 5.37 and 5.22(2, 2 d's J=13.5, AB pNB methylene), 4.73 (1, s, C₃ --H), 4.55 ##STR69##4.16 and 4.00 (2, 2 d's J=11.5, AB C₂ --CH₂ --O), and 1.41 (3, s C₂--CH₃).

Anal. Calc'd for C₂₄ H₂₄ N₄ O₉ S: C, 52.93; H, 4.44; N, 10.29; s, 5.89;Found: C, 52.82; H, 4.51; N, 10.11; s, 5.78.

EXAMPLE 7 (2R,3S,5R,6R)2-Carbamoyloxymethyl-2-methyl-6-phenoxyacetamidopenam-3-carboxylic Acid

The p-nitrobenzyl ester of the title compound (1.09 g 2.0 mmol) wasadded to a prehydrogenated suspension of 10% palladium on charcoal (0.55g) in ethyl acetate (50 ml) and 0.4% aqueous potassium bicarbonate (35ml). The whole was shaken at 50 psi hydrogen pressure for 1.4 hours andfiltered, with 0.4% bicarbonate (2×3 ml)and water (5 ml) washes. Thelayers were separated and the aqueous phase was washed with CHCl₃ (20ml), combined with an H₂ O back extract (10 ml), and stirred with CH₂Cl₂ (25 ml) during pH adjustment to 2.0 with 35% sulfuric acid. Theorganic phase was separated, washed with pH 2 buffer (10 ml), dried over4A sieves, polish filtered and concentrated in vacuo to a colorless foam(0.25 g) in 29% yield; nmr 100 MHz (CDCl₃ --D₂ O) ppm 7.3 (2, m,meta--H's), 7.0 (3 m, o,p--H's), 5.7 (2, m's, C₅,C₆ --H's), 4.74 (1, s,C₃ --H), 4.59 ##STR70## 4.19 and 4.04 (1 ea, ABq, J=11.5, C₂ --CH₂ O),1.58 (3, s, C₂ --CH₃).

EXAMPLE 8 (2R,3S,5R,6R)2-(N-Acetyl)carbamoyloxymethyl-2-methyl-6-[3-(2,6-dichlorophenyl)-5-methylisoxazol-4-ylamido]penam-3-carboxylicAcid p-Nitrobenzyl Ester

A suspension of (1S,3S,5R,6R)2,2-dimethyl-6-[3-(2,6-dichlorophenyl)-5-methylisoxazol-4-ylamido]penam-3-carboxylicacid-1-oxide p-nitrobenzyl ester (6.21 g, 10.0 mmol) in dioxane(50 ml)with acetyl isocyanate (2.3 ml, 30 mmol) was stirred at reflux undernitrogen for 6 hours. The resulting clear solution was concentrated invacuo to a light orange foam. Chromatography of this foam on silica gel(500 g) with methylene chloride:acetone; 9:1; v:v gave 3 majorfractions, the Δ³ cephem, the title penam, and the cepham analog. Thepenam was obtained by concentration as an off-white foam in 44% yield(3.12 g): mp 85°d; nmr (CDCl₃) 100 MHz ppm 8.23 (d, J=8.5 Hz)overlapping 8.17 ##STR71## 7.53 (d, J=8.5) overlapping 7.48 (s, 5 total1/2pNB AB and other aromatics), 6.22 (1, d, J=9.5, C₆ --NH) 5.79 (1, dd,J=4, 9.5, C₆ --H), 5.58 (1, d, J=4, C₅ --H), 5.39 and 5.21 (2, 2 d's,J=13, AB pNB methylene, 4.72 (1, s, C₃ --H) 4.14 (1, d, J=11, C₂--CHHO), 3.62 (1, d, J=11, C₂ --CHHO), 2.81 (3, s, isox--CH₃), 2.31##STR72## and 1.39 (3, s, C₂ --CH₃).

Anal. Calc'd for C₂₉ H₂₅ N₅ O₁₀ SCl₂ : C, 49.30; H, 3.57; s, 4.54; Cl,10.04. Found: C, 49.31; H, 3.83; s, 4.30; Cl, 10.17.

EXAMPLE 9 (2R,3S,5R,6R)2-(N-Acetyl)-carbamoyloxymethyl-2-methyl-6-phenylacetamidopenam-3carboxylic Acid p-Nitrobenzyl Ester

A solution of (1S,3S,5R,6R)2,2-dimethyl-6-phenylacetamidopenam-3-carboxylic acid -1-oxidep-nitrobenzyl ester (4.85 g, 10.0 mmol) and acetyl isocyanate (2.3 ml,30 mmol) in dioxane (50 ml) was refluxed under nitrogen for 7 hours. Thelight orange solution was concentrated in vacuo to a foam which waschromatographed on silica gel (500 g) with methylene chloride:acetone;9:1, v:v. Two major bands were eluted; the first was the Δ³3-methylcephem (28%, 1.29 g) and the second was the title compoundobtained in 45% yield (2.56 g) as an off-white foam: mp 83°-85°; nmr 100MHz (CDCl₃) ppm 8.24 (2, d, J=9 Hz, 1/2aromatic AB pNB), 7.61 (2, d,J=9, 1/2 pNB AB), 7.28 (5, s, phenyl), 5.54 (2, m's C₆ --C₅ --H's), 5.40(2, br s, pNB methylene), 4.91 (1, s, C₃ --H), 4.27 1, d, J=12, 1/2 C₂--CHHO AB), 4.08 (1, d, J=12, 1/2C₂ --methylene AB), 3.12 ##STR73## 2.12(3, s, acetyl), and 1.41 (3, s, C₂ --CH₃).

Anal. Calc'd. for C₂₆ H₂₆ N₄ O₉ S: C, 54.73; H, 4.59; N, 9.82. Found: C,54.53; H, 4.79; N, 9.82.

EXAMPLE 10 (2R,3S,5R,6R)2-(N-Acetyl)carbamoyloxymethyl-2-methyl-6-(5-methyl-3-phenyl-4-isoxazolyl)amidopenam-3-carboxylicAcid p-Nitrobenzyl Ester

A suspension of (1S,3S,5R,6R)2,2-dimethyl-6-(5-methyl-3-phenyl-4-isoxazolyl)amidopenam-3-carboxylicacid-1-oxide p-nitrobenzyl ester (5.53 g, 10.0 mmol) was treated inrefluxing dioxane (50 ml) with acetyl isocyanate (2.3 ml, 30 mmol) for 6hours. The unreacted ester (1.26 g, 2.3 mmol) was removed by filtrationand the filtrate was concentrated in vacuo to a dark yellow foam whichwas chromatographed on silica gel (500 g) with methylenechloride:acetone, (9:1; v:v). The product fraction was concentrated invacuo to a colorless foam (1.02 g) in 20.5% yield; nmr 100 MHz (CDCl₃)ppm 9.20 (2, d, J=8.5 Hz, 1/2pNB AB), 8.84 ##STR74## 8.50 with 8.46 (7,m's, 1/2pNB and phenyl H's), 8.23 (1, br d, J=9, C₆ --NH), 5.76 (1, dd,J=4, 9, C₆ --H), 5.51 (1, d, J=4, C₅ --H), 5.26 and 5.19 (2, ABq, J=13,pNB--CH₂), 4.64 (1, s, C₃ --H), 4.03 (1, d, J=11.5, 1/2 AB C₂ --CH₂--O), 3.53 (1, d, J=11.5, 1/2 AB C₂ --H₂ O), 2.76 (3, s, oxazolyl-Me),2.27 ##STR75## and 1.33 (3, s, C₂ --CH₃).

EXAMPLE 11 (A) (2R,3S,5R,6R)2-(N-Acetyl)carbamoyloxymethyl-2-methyl-6-(2-ethoxynaphthoylamido)penam-3-carboxylicAcid p-Nitrobenzyl Ester

A mixture of acetyl isocyanate (2.3 ml, 30 mmol), 1S,3S,5R,6R)2,2-dimethyl-6-(2-ethoxynaphthoylamido)penam-3-carboxylic acid-1-oxidep-nitrobenzyl ester (5.66 g, 10.0 mmol) and dioxane (50 ml) was refluxedfor 6 hours and concentrated in vacuo. The concentrate waschromatographed on silica gel (500 g) with methylene chloride:acetone,9:1, v:v. Four major fractions were obtained; the Δ³ 3-methyl cepham,the starting sulfoxide, the title penam, and the cepham analog (in orderof elution). The "penam" fractions were concentrated in vacuo to a paleyellow foam in 23% yield (1.47 g): mp, 100° d; nmr (CDCl₃) 100 MHz ppm8.29 (2, d, J=9 Hz, 1/2 aromatic AB pNB), 8.0-7.1 (10, m's,aromatics+NH's), 6.09 (1, dd, J=9, 4, C₆ --H), 5.77 (1, d, J=4, C₅ --H),5.37 and 5.23 (2, 2, d's, J=13 Hz, AB pNB methylene), 4.73 (1, s, C₃--H), 4.32 (q, J=7) over 4.29 (d, J=11, 3 total CH₂ CH₃ and 1/2C₂--CHHO), 3.91 (1, J=11, C₂ --CHHO), 2.14 ##STR76## and 1.42 (6, s, witht, J=7, C₂ --CH₃ and CH₂ CH₃).

Anal. Calc'd for C₃₁ H₃₀ N₄ O₁₀ S: C, 57.21; H, 4.65; N, 8.61; S, 4.93.Found: C, 57.12; H, 4.72; N, 8.30; S, 4.87.

(B)(3S,4R,5R,6R)-3-(N-Acetyl)carbamoyloxy-3-methyl-7-(2-ethoxynaphthoylamido)cepham-4-carboxylicAcid p-Nitrobenzyl Ester

The final product fractions of Step A, above, yielded the title compoundas a pale yellow foam in 4.1% (0.27 g) yield; nmr (CDCl₃) 100 MHz ppm8.3-7.1 ##STR77## 6.90 (1, br d, J=8.5 Hz, C₇ --NH), 6.14 (1, dd, J=4.5,8.5, C₇ --H), 5.35 (2, s, pNB CH₂), 5.16 (1, d, J=4.5, C₆ --H), 4.26 (2,q, J=7, OCH₂ CH₃), 3.60 (1, br d, J=18, 1/2AB C₂ --CH₂), 3.22 (1, d,J=18, 1/2AB), 2.18 ##STR78## and 1.58 (br s) with 1.49 (t, J=7, total 6protons, C₃ --CH₃ and CH₂ CH₃).

EXAMPLE 12 (2R,3S,5R,6R)2-Carbamoyloxymethyl-2-methyl-6-[3-(2,6-dichlorophenyl)-5-methyl-4-isoxazolyl]amidopenam-3-carboxylicAcid p-Nitrobenzyl Ester

A mixture of (1S,3S,5R,6R)2,2-dimethyl-6-[3-(2,6-dichlorophenyl)-5-methyl-4-isoxazolyl]amidopenam-3-carboxylicacid-1-oxide p-nitrobenzyl ester (6.21 g, 10.0 mmol) and trichloroacetylisocyanate (3.3 ml, 32 mmol) in dioxane (50 ml) was refluxed for 3.5hours under nitrogen. The light yellow solution was cooled, andconcentrated to an oil which was stirred with methanol (100 ml). Themethanol solution was decanted, with a methanol wash (2×10 ml), from alittle residual oil, and was adjusted to pH 7.4 with 5% sodiumbicarbonate. The pH was held at 7.4 to 7.5 with 3% sulfuric acid for 2hours and the reaction was quenched in methylene chloride (200 ml) andwater (100 ml). The rich organic layer was washed with water (100 ml),combined with a back extract (CH₂ Cl₂, 50 ml), dried (4A sieves), polishfiltered, and concentrated in vacuo to a yellow oil.

Chromatography of the oil on silica gel (500 g) with methylenechloride:acetone, (9:1; v:v) gave four zones. Following the void volume,fractions of 25 ml were collected; tubes 6-16 containing the Δ³3-methylcephem, tubes 10-18 small amounts of starting sulfoxide, tubes20-44 the title penam, and tubes 46-74 the corresponding cepham. Tubes21-40 of the penam fraction were combined and concentrated in vacuo to aclear light cream foam; 29.7% yield (1.97 g): nmr 100 MHz (CDCl₃) ppm8.13 (2, d, J=8.5 Hz, 1/2aromatic AB pNB), 7.53 (d, J=8.5) with 7.47(tight m, total 5, 1/2aromatic AB and dichlorophenyl H's), 6.37 (1, d,J=9.2, C₆ --NH), 5.80 (1, dd, J=4.0, 9.2, C₆ --H), 5.55 (1, d, J=4.0, C₅--H), 5.37 and 5.20 (2, d's, J=12.8, pNB methylene AB), 5.0 (2, br s,NH₂), 4.68 (1, s, C₃ --H), 4.10 (1, d, J=11.5, 1/2AB C₂ --CH₂ O), 3.56(1, d, J=11.5, 1/2AB C₂ --CH₂), 2.81 (3, s, isoxazolyl CH₃), 1.37 (3, s,C₂ --CH₃).

EXAMPLE 13 (2R,3S,5R,6R)6-(4-Nitrobenzyloxycarbonyl)amino-2-carbamoyloxymethyl-2-methylpenam-3-carboxylicAcid p-Nitrobenzyl Ester

A mixture of (1S,3S,5R,6R)6-(4-nitrobenzyloxycarbonyl)amino-2,2-dimethylpenam-3-carboxylicacid-1-oxide p-nitrobenzyl ester (8.19 g, 15.0 mmol), trichloroacetylisocyanate (5.0 ml, 7.9 g, 42 mmol) and dioxane (75 ml) was refluxedunder nitrogen for 3.5 hours and concentrated in vacuo to a light brownoil. The oil was stirred with warm methanol (150 ml) for 0.5 hour andthe solution was decanted from a small amount of dark residue. Themethanol solution was adjusted to pH 7.4 with 5% sodium bicarbonate andheld at pH 7.4-7.5 with 3% sulfuric acid during a 2.0 hour stirringperiod. The mixture was then distributed between methylene chloride (250ml) and water (100 ml). The organic layer was washed with water (100ml), combined with a CH₂ Cl₂ back-extract (100 ml), dried (4A molecularsieve), polish filtered, and concentrated in vacuo to a light brown oil.

The oil was chromatographed on silica gel (500 g) with methylenechloride:acetone (9:1 v:v) to give three major bands; (in elution order)the Δ³ 3-methylcephem, the title penam and the corresponding cepham. Thepenam fraction was concentrated in vacuo to a pale yellow foam in 19.7%(1.74 g) overall yield; nmr 100 MHz (CDCl₃) 8.23 (d, J=9.5 Hz) with 8.18(d, J=8.5, total 4, 1/2 (2) aromatic AB's), 7.55 (d, J=9.5) and 7.50 (d,J=8.5, total 4, other 1/2(2) aromatic AB's), 6.36 (1, d, J=9.5, C₆--NH), 5.63 (1, d, J=4, C₅ --H), 5.48 (˜1, dd, J=4, 9.5, C₆ --H), 5.31(m) and 5.24 (s, ˜4, pNB methylenes), 5.10 (˜2, br s, NH₂), 4.73 (1, s,C₃ --H), 4.25 (1, d, J=12, 1/2C₂ methylene AB), 3.94 (1, d, J=12, other1/2 C₂ CH₂ O AB), and 1.44 (3, s, CH₃). Recrystallization of a portionfrom ether-methylene chloride returned small colorless needles: mp80°-81°.

Anal. Calc'd for C₂₄ H₂₃ N₅ O₁₁ S: C, 48.89; H, 3.93; N, 11.88. Found:C, 48.82; H, 3.97; N, 11.86.

EXAMPLE 14 (2R,3S,5R,6R)6-Amino-2-carbamoyloxymethyl-2-methylpenam-3-carboxylic Acid

A suspension of 10% palladium on charcoal (0.50 g) in ethyl acetate (25ml) and aqueous potassium bicarbonate (0.4%, 22.5 ml, 0.10 g inorganics)was prehydrogenated at 50 psi hydrogen for 15 minutes. The suspensionwas charged under nitrogen with (2R,3S,5R,6R)6-(4-nitrobenzyloxycarbonyl)amino-2-carbamoyloxymethyl-2-methylpenam-3-carboxylicacid p-nitrobenzyl ester (0.54 g, 0.9 mmol) and the whole was shaken at50 psi hydrogen pressure for 1.2 hours. The mixture (pH 5.0) wascentrifuged and the aqueous phase was washed with methylene chloride(2×15 ml), combined with a water back extract (10 ml), and concentratedto about a 2 ml volume. The rich aqueous phase was diluted withdeuterium oxide (4 ml) frozen on dry-ice and lyophilized to give a lightyellow solid (0.25 g; theory=0.25 g+inorganics 0.10 g) in 66% productyield; nmr 100 MHz (D₂ O) ppm 4.63 (1, d, J=4.0 Hz, C₆ --H), 4.46 (1, s,C₃ --H), C₅ --H under HOD, 4.18 (1, d, J=11.5, 1/2AB C₂ --CHH--O), 4.01(1, l d, J=11.5, C₂ --CHHO), and 1.53 (3, s, C₂ -- CH₃).

EXAMPLE 15 (3S,4R,6R,7R)7-(4-Nitrobenzyloxycarbonyl)amino-3-carbamoyloxy-3-methylcepham-4-carboxylicAcid p-Nitrobenzyl Ester

The title compound was eluted as the final fractions in thechromatographic separation of Example 13 in a yield of 1.1% (0.10 g).The product was equal in nmr and tlc characteristics to an analyticalsample prepared in a larger run: mp 79°-80°; nmr 100 MHz (CDCl₃) ppm8.23 (d, J=9.0 Hz) with 8.17 (d, J=8.5, total 4, 1/2 aromatic AB's p-NO₂benzyl), 7.55 (d, J=8.5) with 7.50 (d, J=9.0, total 4, 1/2 aromaticAB's), 6.47 (1, d, J=9.5, C₇ --NH), 5.31 (s) and 5.22 (s) over 5.5-5.2(m's, total 8, benzyl CH₂ 's over C₆ --H, C₇ --H and NH₂), 4.89 (1, s,C₄ --H), 3.54 (1, br d, J=14.5, 1/2AB C₂ HH), 3.29 (1, d, J=14.5, C₂HH), and 1.53 (3, s, C₃ --CH₃).

Anal. Calc'd for C₂₄ H₂₃ N₅ O₁₁ S.1/2H₂ O: C, 48.15; H, 4.04; N, 11.70;S, 5.36. Found: C, 48.24; H, 3.96; N, 11.68; S, 5.20.

EXAMPLE 16 (6R,7R) 3-Methyl-7-phenoxyacetamidoceph-3-em-4-carboxylicAcid Diphenylmethyl Ester

A solution of (1S,3S,5R,6R)2,2-dimethyl-6-phenoxyacetamidopenam-3-carboxylic acid-1-oxidediphenylmethyl ester monohydrate (5.51 g, 10.0 mmol) in dioxane (50 ml)was stirred over Linde 4A molecular sieves (2 g) for 16 hours andfiltered with a dioxane wash (2×15 ml). To the dried solution was addedp-toluenesulfonyl isocyanate (4.3 g, 22 mmol), and the mixture washeated at reflux for 7 hours under nitrogen and then concentrated invacuo to a light orange oil. The residue was distributed betweenmethylene chloride (50 ml) and water-ice (50 ml) with pH adjustment to8.4 using dropwise addition of 50% NaOH, and back washes with CH₂ Cl₂(20 ml) and pH 10 phosphate buffer (20 ml). The combined organicextracts were dried (sieves), polish filtered, and concentrated in vacuoto a light yellow foam. The foam was taken into boiling isopropanol (75ml) and after cooling yielded a glassy solid (6.23 g). A major portionof the solid (5.95 g) was filtered through silica gel (25 g) with CH₂Cl₂ :acetone, 9:1, v/v (120 ml) and the filtrate was concentrated invacuo to a pale yellow solid (4.02 g, 78%). Crystallization of a portion(2.72 g) from isopropanol (40 ml) returned an off-white microcrystallinesolid which was collected, washed with 0° isopropanol (25 ml) and driedin vacuo to give the title compound (1.93 g, 71% recovery, 55% overall).NMR indicated 82% purity, with impurities of p-toluenesulfonamide andisopropanol.

EXAMPLE 17 (6R,7R) 3-Methyl-7-phenoxyacetamidoceph-3-em-4 -carboxylicAcid Diphenylmethyl Ester

A solution of (1S,3S,5R,6R)2,2-dimethyl-6-phenoxyacetamidopenam-3-carboxylic acid-1-oxidediphenylmethyl ester monohydrate in dioxane was dried over Linde 4Amolecular sieves and an aliquot (18 ml, containing 4.1 mmol of theester) was charged with pyridine (0.081 ml, 1.0 mmol), acetyl bromide(0.073 ml, 1.0 mmol), and acetyl isocyanate (1.1 ml, 12 mmol). Thesolution was heated at reflux under nitrogen for 4 hours andconcentrated in vacuo to a brown glass which was filtered through silicagel (12 g) with 9:1, v/v methylene chloride:acetone (75 ml) to removecolor and impurities. The filtrate was concentrated in vacuo to a yellowfoam (1.85 g, 88%). A portion of this solid (1.61 g) was crystallizedfrom hot isopropanol (20 ml) to return the title compound as a yellowsolid (1.51 g, 94% recovery, 83% overall) of 90+% purity by n.m.r.

EXAMPLE 18 (2R,3S,5R,6R)6-Amino-2-carbamoyloxymethyl-2-methylpenam-3-carboxylic Acidp-Nitrobenzyl Ester

A solution of (2R,3S,5R,6R)2-(N-acetyl)carbamoyloxymethyl-2-methyl-6-phenoxyacetamidopenam-3-carboxylicacid p-nitrobenzyl ester (1.17 g, 2.0 mmol) in methylene chloride (10ml) at -40° was charged with dimethylaniline (1.03 ml, 8.0 mmol) andphosphorous pentachloride (0.92 g, 4.4 mmol). The solution was stirredat -35° to -40° for 30 minutes and cold (˜-35°) methanol (4.1 ml, 100mmol) was added dropwise. The pale green solution was stirred at -35° to-40° for 2 hours and then quenched into ice-water (10 ml). The pH wasadjusted to 1.7 with conc. ammonia and the layers were separated. Theaqueous was washed with CH₂ Cl₂ (5 ml), combined with a waterback-extract (5 ml), and stirred with CH₂ Cl₂ (10 ml) during pHadjustment to 6.5 with ammonia. The organic phase was withdrawn, washed(5 ml, H₂ O), combined with a back-extract (CH₂ Cl₂, 10 ml), dried (4Asieves), filtered, concentrated to 4 ml and diluted with heptane (10ml). The suspension was concentrated to 8 ml and the liquids weredecanted. The solids were treated with CH₂ Cl₂ (4 ml) and heptane (10ml) in the same fashion, and the product was washed with heptane anddried to an off-white solid (0.28 g) 34%; nmr 100 MHz CDCl₃ --D₂ O δ8.24(2, d, J=8.5 Hz, 1/2 pNB AB), 7.56 (2, d, J=8.5, pNB, AB), 5.68 (1, brdJ=4, C₅ --H) 5.32 (2, s, benzyl CH₂), 4.76 (1, s, C₃ --H) 4.55 (HODoverlapping C₆ --Hd), 4.16 and 3.97 (2, ABq J=11.5 C₂ --CH₂ --O), 1.43(3, s, C₃ --CH₃), with 2.36 (3/4 , s, ##STR79## of impurity N-acetylanalog; ˜25 mol %).

EXAMPLE 19 (6R,7R) 3-Methyl-7-phenoxyacetamidoceph-3-em-4-carboxylicAcid Diphenylmetyl Ester

(1S,3S,5R,6R) 2,2-Dimethyl-6-phenoxyacetamidopenam-3-carboxylicacid-1-oxide diphenylmethyl ester (25.00 gms, 45.41 mmoles) wasdissolved in sieve-dried, peroxide-free dioxane (250 mls) at 25° C. withgood agitation. To this solution, in order, were added pyridine (10.99mls, 10.78 gms, 136.22 mmoles), acetyl bromide (0.67 mls, 1.12 gms, 9.08mmoles) and dimethylsilyl diisocyanate (16.14 gms, 113.51 mmoles), andthe slurry was heated to reflux (ca. 100° C.) for 4 hours. The dioxaneslurry was then cooled to 25° C., filtered, and concentrated in vacuo at50° C. to a heavy oil. The oil was taken up in methylene chloride (400mls), stirred for 15 minutes at 25° C., filtered, and concentrated invacuo to dryness. The residue was dissolved in hot 1-butanol (500 mls,ca. 90°-95° C.) and allowed to cool to 25° C. The slurry was cooled to0°-5° C. for 16 hours, filtered, washed with cold butanol (0°-5° C., 100mls), then with Skellysolve B (200 mls), and oven-dried at 45° C. toconstant weight. Yield: 20.2 gms, 86.4% of snow-white crystalline titlecompound. The NMR spectrum was clean and consistent for the desiredstructure, as follows: 80 MHz H' NMR, δ(CD₂ Cl₂) 2.08 (3H, s, CH₃),3.04-3.62 (2H, m, CH₂, J_(AB) =18.1 Hz), 4.55 (2H, s, CH₂), 4.99-5.05(1H, d, β-lactam H, J_(A) =4.7 Hz), 5.74-5.91 (1H, m, β-lactam H, J=4.7Hz), 6.75-7.50 (17H, m, aromatic CH, and NH).

EXAMPLE 20 (6R,7R) 3-Methyl-7-phenoxyacetamidoceph-3-em-4-carboxylicAcid Diphenylmethyl Ester

(1S,3S,5R,6R) 2,2-Dimethyl-6-phenoxyacetamidopenam-3-carboxylicacid-1-oxide diphenylmethyl ester (55.06 gms, 100.00 mmoles) wasdissolved in sieve-dried, peroxide-free dioxane (550 mls) at 25° C. withgood agitation. To this solution, in order, were added pyridine (24.21mls, 23.73 gms, 300.00 mmoles), acetyl bromide (1.48 mls, 2.46 gms,20.00 mmoles) and methylsilyl triisocyanate (89% pure, 21.30 mls, 25.34gms, 133.33 mmoles). The slurry was heated to reflux (ca 100° C.) for 4hours. The reaction mixture was then cooled to 25° C. and filtered, withthe clear yellow filtrate being concentrated in vacuo at 50° C. to ahighly viscous oil. The oil was dissolved in hot 2-propanol (˜80° C.,3000 mls), filtered, and allowed to cool to 25° C. The slurry was cooledto 0°-5° C. for 2 hours, filtered, and washed with 2-propanol (0°-5° C.,400 mls), and oven-dried at 45° C. to constant weight. Yield: 38.6 gms,75% of white crystalline title compound. The 80 MHz H' NMR spectrum wasclean and consistent for the desired structure.

EXAMPLE 21 (2R,3S,5R,6R)2-(N-Acetyl)carbamoyloxymethyl-6-amino-2-methylpenam-3-carboxylic Acidp-Nitrobenzyl Ester

A solution of (2R,3S,5R,6R)2-(N-acetyl)carbamoyloxymethyl-2-methyl-6-phenoxyacetamidopenam-3-carboxylicacid p-nitrobenzyl ester (4.68 gm, 8 mmols) in dry methylene chloride(40 ml) was cooled to -60° under nitrogen. It was charged withdimethylaniline (4.06 gm, 33.5 mmol) and phosphorus pentachloride (3.68gm, 17.7 mmol) and stirred for 30 minutes at -64° to -56°, during whichtime the phosphorus pentachloride dissolved. A solution of dry methanol(8.10 ml) in dry methylene chloride (8.10 ml) was then slowly added at-55° to -45°. The reaction mixture was stirred for 20 minutes at -60° to-55° and then poured into 16 ml of ice-water. The pH was adjusted to 1.7with concentrated ammonia and the layers were separated. The methylenechloride layer was washed with 20 ml of pH 2.0 buffer which wasseparated and combined with the aqueous layer. Methylene chloride (20ml) was added to the combined aqueous layers and the mixture wasadjusted to pH 6.5 with concentrated ammonia. The phases were separated,the water was washed with 20 ml of methylene chloride, and the combinedmethylene chloride layers were dried over molecular sieves. Afterfiltration, the solution was concentrated in vacuo to about 20 ml andthen added dropwise to 400 ml of stirring heptane. The heptane wasdecanted from the solid which precipitated and was replaced by 100 ml offresh heptane. The suspension was thoroughly stirred, filtered, washed,air dried, and finally dried in vacuo. There was obtained 1.66 gm of thetitle product as a white amorphous solid. The purity was estimated fromits nmr spectrum to be about 90%, the remainder being primarily thenon-acetylated material.

EXAMPLE 22 (2R,3S,5R,6R)2-(N-Acetyl)carbamoyloxymethyl-6-amino-2-methylpenam-3-carboxylic Acid

To a prehydrogenated suspension of 10% palladium on carbon (0.83 gm),water-washed ethyl acetate (8.3 ml) and water (4.1 ml) was added(2R,3S,5R,6R)2-(N-acetyl)carbamoyloxymethyl-6-amino-2-methylpenam-3-carboxylic acidp-nitrobenzyl ester (0.83 gm, 1.84 mmol). The mixture was shaken at 50psi hydrogen pressure for 80 minutes and filtered throughDicalite-coated paper. The aqueous phase was separated, concentrated atreduced pressure to remove volatile solvent and gases, frozen andlyophilized. There was obtained 0.38 gm of the title compound as a whiteamorphous solid. Its nmr spectrum was consistent with the desiredproduct.

EXAMPLE 23 (2R,3S,5R,6R)2-(N-Acetyl)carbamoyloxymethyl-6-[(R)-2-Amino-2-phenylacetamido]-2-methylpenam-3-carboxylicAcid p-Nitrobenzyl Ester

A solution of (2R,3S,5R,6R)2-(N-acetyl)carbamoyloxymethyl-6-amino-2-methylpenam-3-carboxylic acidp-nitrobenzyl ester (0.80 gm, 1.77 mmol) in methylene chloride (10 ml)was cooled to 2° and dimethylaniline (0.214 gm, 1.77 mmol) was added. Tothe stirred mixture was added (-)-phenylglycyl chloride hydrochloride(0.392 gm, 1.83 mmol) in two equal portions. The first portion was addedat 2° and the reaction mixture was gradually warmed to 20° over a 90minute period. The reaction did not appear to begin at the lowertemperatures. The second portion of the acid chloride was added at 20°and the reaction mixture was stirred at room temperature for 41/2 hours.Water (10 ml) was added and, with thorough mixing, the pH was adjustedto 1.7. The layers were separated, the water layer was washed withmethylene chloride, and the methylene chloride layer was washed with pH2.0 buffer. The aqueous layers were combined, adjusted to pH 7.0 with10% KOH solution, and extracted with methylene chloride (2×10 ml). Themethylene chloride extracts were combined, dried over molecular sievesand concentrated in vacuo to about 15 ml. This solution was addeddropwise to 300 ml of stirring heptane and produced a fine whiteamorphous solid. This was removed by filtration and dried to give 0.61gms of the title product. The purity was estimated from its nmr spectrumto be about 60%.

EXAMPLE 24 (2R,3S,5R,6R)2-(N-Acetyl)carbamoyloxymethyl-6-[(R)-2-amino-2-phenylacetamido]-2-methylpenam-3-carboxylicAcid

To a prehydrogenated suspension of 10% palladium on carbon (0.59 gm),water-washed ethyl acetate (6.0 ml) and water (3.0 ml) was added(2R,3S,5R,6R)2-(N-acetyl)carbamoyloxymethyl-6-[(R)-2-amino-2-phenylacetamido]-2-methylpenam-3-carboxylicacid p-nitrobenzyl ester (0.59 gm. 1.06 mmol). The mixture was shaken at50 psi hydrogen pressure for 3 hours at 25° and then filtered throughDicalite-coated paper. The aqueous phase was separated, concentrated atreduced pressure to remove volatile solvent and gases, frozen andlyophilized. There was obtained 0.30 gm of the title compound as anamorphous solid. The purity was estimated from its nmr spectrum to be60-70%.

EXAMPLE 25 Percentage OF Penam, Cepham And Cephem Formed In The ReactionOF [1S,3S,5R,6R] 2,2-Dimethyl-6-phenoxyacetamidopenam-3-carboxylicAcid-1-oxide Diphenylmethyl Ester With Different Isocyanates UnderVarying Conditions And With Varying Subsequent Treatment Of The InitialProduct

A 5% solution of [1S,3S,5R,6R]2,2-dimethyl-6-phenoxyacetamidopenam-3-carboxylic acid-1-oxidediphenylmethyl ester in dioxane was prepared. Aliquots of the abovesolution containing 5.51 gms (10 mmols) of the penicillin sulfoxideester were charged with 30 mmols (300 mole %) of the indicatedisocyanate (and, where indicated, with pyridine and/or acetyl bromide).The solutions were refluxed under nitrogen for 4 hours and thenconcentrated in vacuo to dryness. When indicated, portions of theresulting products were further treated with base or filtered throughsilica gel with methylene chloride:acetone (9:1, v:v), and concentratedto dryness. The residues were analyzed for approximate percentages ofpenam, cepham and Δ³ -cephem by integration of the nmr methyl groupsignals at ca. δ1.2 for the penams, ca. δ1.5 for the cephams and ca.δ2.11 for the Δ³ -cephems.

    ______________________________________                                         PyridineMole %                                                                       ##STR80##      Penam%   Cepham%                                                                              Cephem%                                ______________________________________                                        p-Toluenesulfonyl isocyanate                                                  (a)    0        0         57     41     2                                     (b)    Product of (a) treated                                                                       0        7      93                                             in methylene chloride                                                         with tetramethylguan-                                                         idine; latter then                                                            removed with water                                                            washes.                                                                (c)    Product of (a) 0        92     8                                              filtered through                                                              silica gel.                                                            Methanesulfonyl isocyanate                                                    (d)    0        0         63     27     10                                    (e)    20       0         57     9      34                                    (f)    50       0         50     0      50                                    (g)    Product of (f) 15       0      85                                             filtered through                                                              silica gel.                                                            (h)    Product of (d) in                                                                            10       20     70                                             methylene chloride                                                            washed with pH 8.5                                                            water and held 2 hrs.                                                  (i)    Product of (d) 55       0      45                                             treated in methylene                                                          chloride with dimethyl-                                                       formamide; latter                                                             removed with water                                                            washes                                                                 (j)    Product of (d) 45       30     25                                             filtered through                                                              silica gel.                                                            Trichloroacetyl isocyanate                                                    (k)    0        0         26     56     18                                    Acetyl isocyanate                                                             (l)    0        0         70     25     5                                     (m)    50       0         70     25     5                                     (n)    0        20        68     30     2                                     (o)    25       25        0      10     80                                    Methoxycarbonyl isocyanate                                                    (p)    0        0         37     38     0                                     ______________________________________                                         Note:                                                                         Product (o) also contained about 10% of an unidentified impurity appearin     at ca. δ 1.6.                                                           Product (p) also contained about 25% of an unidentified impurity appearin     at ca. δ 1.9.                                                      

EXAMPLE 26 Preparation of [6R,7R]3-Methyl-7-phenoxyacetamidoceph-3-em-4-carboxylic Acid DiphenylmethylEster From [1S,3S,5R,6R]2,2-Dimethyl-6-phenoxyacetamidopenam-3-carboxylic Acid-1-oxideDiphenylmethyl Ester Utilizing Various Isocyanates And Varying Amountsof Pyridine And Acetyl Bromide as Catalysts

A solution of 55 gm (100 mmol) of [1S,3S,5R,6R]2,2-dimethyl-6-phenoxyacetamidopenam-3-carboxylic acid-1-oxidediphenylmethyl ester in dioxane (500 ml) was dried over Linde 4A sieves(50 gm). Aliquots (25 ml each; 5 mmols) were withdrawn, charged with 15mmoles (300 mole %) of the indicated isocyanate and the indicated molepercentage of pyridine and acetyl bromide. The solutions were refluxedunder nitrogen for 6 hours and then concentrated in vacuo to dryness.The residues were filtered through silica gel (10 gm) with methylenechloride:acetone (9:1; v:v). The filtrates were concentrated in vacuo tolight yellow foams which were analyzed by liquid chromatography againstauthentic [6R,7R] 3-methyl-7-phenoxyacetamidoceph-3-em-4-carboxylic aciddiphenylmethyl ester as a standard. Listed below are the % weight yield,% activity and % activity yield for each reaction.

    ______________________________________                                         PyridineMole %                                                                         ##STR81##  Yield% Weight                                                                           Activity%                                                                            Yield% Activity                         ______________________________________                                        Methanesulfonyl isocyanate                                                    10        5         110       47.2   52                                       30       25         110       47.8   53                                       50       25         130       37.5   49                                       100      50         120       27.6   33                                       Trichloroacetyl isocyanate                                                    20       10          95       37.4   36                                       25       20         165       28.2   48                                       50       25         110       41.3   45                                       Silicon tetraisocyanate                                                       20       10         120       43.2   52                                       30       25         120       51.0   61                                       ______________________________________                                    

I claim:
 1. A compound of the formula ##STR82## in which Q is ##STR83##R¹ is hydrogen and R² is hydrogen, a conventional amino-protectinggroup, phenoxyacetyl, phenylacetyl, 2-amino-2-phenylacetyl,2-amino-2-(p-hydroxyphenyl)acetyl, naphthoyl, 2-ethoxynaphthoyl,5-methyl-3-phenyl-4-isoxazolylcarbonyl,5-methyl-3-(o-chlorophenyl)-4-isoxazolylcarbonyl or3-(2,6-dichlorophenyl)-5-methyl-4-isoxazolylcarbonyl, or R¹ and R²,taken together with the nitrogen atom to which they are attached, form aphthalimido group, a succinimido group or a group of the formula##STR84## in which R¹¹ is phenyl or p-hydroxyphenyl; R⁶ is hydrogen,(lower)alkanoyl, chloroacetyl, dichloroacetyl, trichloroacetyl orp-toluenesulfonyl; andR⁷ is hydrogen or a conventionalcarboxyl-protecting group; or, when R⁷ is hydrogen, a nontoxicpharmaceutically acceptable salt or physiologically hydrolyzable esterthereof.
 2. A compound of claim 1 in which R⁷ is hydrogen, and R¹ andR², taken together with the nitrogen to which they are attached, form agroup of the formula ##STR85## in which R¹¹ is phenyl orp-hydroxyphenyl; or a pharmaceutically acceptable salt orphysiologically hydrolyzable ester thereof.
 3. A compound of claim 2 inwhich R⁶ is hydrogen; or a pharmaceutically acceptable salt orphysiologically hydrolyzable ester thereof.
 4. A compound of claim 1having the formula ##STR86## in which R¹¹ is phenyl or p-hydroxyphenyl;or a pharmaceutically acceptable salt or physiologically hydrolyzableester thereof.
 5. A compound of claim 1 having the formula ##STR87## inwhich R¹⁵ is benzyl, p-hydroxybenzyl, 5-methyl-3-phenyl-4-isoxazolyl,5-methyl-3-(o-chlorophenyl)-4-isoxazolyl,3-(2,6-dichlorophenyl)-5-methyl-4-isoxazolyl or 2-ethoxynaphthyl, or anontoxic pharmaceutically acceptable salt or physiologicallyhydrolyzable ester thereof.
 6. A compound of claim 1 having the formula##STR88## wherein R¹⁵ A(CH₂)_(s) --is phenoxymethyl, or a nontoxicpharmaceutically acceptable salt or physiologically hydrolyzable esterthereof.
 7. A compound of claim 1 having the formula ##STR89## in which##STR90## is α-aminobenzyl or α-amino-p-hydroxybenzyl, or a nontoxicpharmaceutically acceptable salt or physiologically hydrolyzable esterthereof.